July 22, 2015 -- New results from ongoing clinical trials have fueled hopes for a class of Alzheimer’s drugs that target the buildup of sticky plaque in the brain linked to the disease.
The data, presented Wednesday to a standing-room-only crowd of doctors and patients at the Alzheimer’s Association International Conference 2015, suggest -- on paper, at least -- that the drugs may slow the decline of people who are treated early in the course of the disease.
But experts who were not involved in the studies say the drugs will likely be pricey, while their benefits appear to be small -- perhaps so slight that people with Alzheimer's might not notice improvements in their ability to think or function in their daily lives.
“Will we get enough bang for our buck?” said Paul Rosenberg, MD, associate director of the Memory and Alzheimer’s Treatment Center at Johns Hopkins Hospital.
But the drugs will continue to be tested, and it could be that larger benefits will become more apparent over time, especially if they can stabilize patients by slowing their decline, said Sam Gandy, MD, PhD, associate director of the Mount Sinai Alzheimer’s Disease Research Center.
“Maybe in 1, 2, or 3 years the treatment will be meaningful, but we can't know that until longer trials are completed,” said Gandy, who was also not involved in the research.
Five million Americans have Alzheimer’s, and that number is expected to climb as the population ages. Current drugs help symptoms, but their benefits wear off over time as the disease marches on, and people inevitably get worse as the disease gradually lays waste to the brain.
The experimental medications target sticky protein pieces called beta amyloid in the brain. Beta amyloid forms telltale plaques that can be seen on brain scans of people with Alzheimer’s disease.
The idea was that getting rid of some of these protein pieces might slow or even reverse the underlying disease. And the drugs, called aducanumab, gantenerumab, and solanezumab, appear to do exactly what they were designed to do.
The problem is that getting rid of beta amyloid doesn’t seem to hold as much benefit for patients -- especially those in the middle and later stages of the disease -- as researchers hoped.
Slowing Alzheimer’s in Its Early Stages
In two large clinical trials, solanezumab failed to show any benefits for patients compared to a placebo. But there were hopeful signs in people with mild Alzheimer’s.
Rather than give up on solanezumab, Eli Lilly, the company developing the drug, decided to keep testing it, focusing on people who had earlier stages of the disease when they started taking the medication.
They gave all the mild patients in the two failed studies -- both those who had been taking a placebo, and those taking solanezumab -- the option to continue to on the study medication.
Those patients, more than 1,300 in total, have now been participating in the studies of the drug for 3 and a half years.
People who had been taking the placebo, but who switched to the drug after 18 months, were considered to have been delayed on their start of the medicine. Researchers were curious to see whether those people would eventually see the same benefits as the patients who had been continuously taking the drug over time.
If the people who were delayed in starting solanezumab never caught up to the benefits in patients who had continuously taken the drug, that would indicate that the medicine had some effect on the underlying biology behind the disease.
After 2 more years, results suggest that the “delayed start” patients don’t catch up, suggesting that the drug alters the course of the disease.
“Think about a disease that has a 10-year span. We’re talking about delaying progression to [a nursing home] or to loss of ability to communicate with family,” said Paul Aisen, MD, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California.
But the differences for patients were small -- about two points or less on tests of thinking, memory, and activities of daily living.
In addition to the conference presentation, the results of the solanezumab study were simultaneously published in the journal Alzheimer’s & Dementia: Translational Research and Clinical Interventions.
“Overall, the changes we’re making are modest. We have to be honest about that,” said Philip Scheltens, MD, PhD, director of the Alzheimer’s Center at the VU University Medical Center in Amsterdam.
Scheltens is testing a drug called gantenerumab that proved to reduce both beta amyloid and another toxic protein called tau in people with Alzheimer’s. But that drug also showed no benefits for patients -- they didn’t do any better on tests of thinking and memory or function in their daily lives than people who were taking a placebo. Scheltens thinks that might be because researchers haven’t been testing a high enough dose of the drug.
“On a disease-modifying therapy, people don’t notice that they’re being treated because over time, the gradual differences are so slowly changing, you don’t know how to compare yourself with where you are a year ago,” he said.
Solanezumab is given through a vein (IV) every 4 weeks, and it has some side effects, including headaches and signs of brain swelling that can be detected on brain scans. Those side effects were considered to be manageable, though. Also, the effect of "biologic" drugs like these can also wear off over time if the immune system starts to react to them.
Roughly 50% of patients have dropped out of the study over time. These are people who know they have Alzheimer’s disease -- an illness which is ultimately fatal -- and are getting a cutting-edge medication for free. Generally, if people are seeing benefits from experimental drugs like these, they clamor to stay in clinical studies so they can continue to have access to the drug.
But researchers disputed that notion. They said the high drop-out rate was to be expected in a clinical trial setting where older patients were being asked to have regular tests and brain scans.
“That is not surprising to us at all. I think it reflects age, other illnesses, and the burden of study procedures that all come together to cause people to drop out,” said Aisen.
When asked if he thought people with Alzheimer's would be willing to pay large amounts of money to go on a drug that offers little apparent benefit and to stay on that medicine indefinitely, Aisen said, “I do.”
Another drug, called aducanumab, is still in the earliest stages of clinical testing. In those trials, researchers are still trying to determine the best dose to give people.
Similar to solanezumab, aducanumab showed slight benefits on tests of thinking and memory on the highest dose of the drug.
The differences were in the range of one to two points compared to placebo.
On that dose, though, about a third of people reported headaches, visual disturbances, and confusion.
Based on those results, Jeff Sevigny, MD, senior medical director of neurodegenerative disorders at Biogen, the company that’s developing the drug, said the company is already screening patients for longer and larger studies of the drug.