Daniel Gibbs had received only four monthly doses of Biogen’s experimental Alzheimer’s drug in a clinical trial in 2017 when he ended up in an intensive care unit. He had an excruciating headache, and his blood pressure was so high that doctors thought he might be having a stroke.
It turned out that the retired Portland, Ore., neurologist ― who had treated Alzheimer’s patients before he was diagnosed with the disease himself in 2015 ― was experiencing some of the worst reported side effects of the drug. Doctors prescribed medicines to lower his blood pressure, which reached 206/116, and later to reduce brain swelling. But for weeks afterward, he struggled to read, follow conversations, and do simple math. He recovered but never again took the Alzheimer’s drug.
Much of the controversy surrounding the medication, called Aduhelm, has centered on conflicting trial data about whether it slows cognitive decline, its $56,000 annual cost, and the unusual process that led to its June approval. But for all the attention focused on the disputed benefits of the Cambridge biotechnology firm’s medicine, Gibbs says an important aspect of Aduhelm has been downplayed ― its risks.
The drug reduces a sticky protein called amyloid that clumps into plaques in the brains of people with Alzheimer’s. Some doctors believe amyloid buildup causes cognitive impairment, although that’s unproven and fiercely contested. What’s not in dispute is this: About 40 percent of patients who received the highest dose in two late-stage trials later showed abnormalities on MRI scans, irregularities that indicated brain swelling or tiny hemorrhages.
More than three-quarters of those “amyloid-related imaging abnormalities,” or ARIA, caused no symptoms. But about 6 percent of patients on the highest dose had to stop taking the drug. Biogen acknowledges that swelling in particular is common, but says it usually goes away on its own and that doctors can manage ARIA with MRI scans during treatment.
“I fault Biogen for being dismissive about the ARIA,” said Gibbs, 70, who was hospitalized before he got halfway to the dosage of 10 milligrams per kilogram that the Food and Drug Administration recommends patients build up to. “I had a severe, potentially life-threatening reaction to the drug.”
Portland doctors successfully treated Gibbs’s symptoms after consulting with researchers at the University of California San Francisco trial site where he received monthly intravenous infusions. He doubts Adulhelm’s side effects will be managed as well when doctors prescribe it in less tightly controlled settings. Biogen expects patients will receive infusions at 900 US clinics and hospitals.
“I would argue that in the first year or so, administration of the drug should be limited to [providers] with experience with the drug,” Gibbs said, “not just any guy with a shingle.”
Gibbs vividly described his experience in a recently published book he wrote called “A Tattoo on My Brain: A Neurologist’s Personal Battle Against Alzheimer’s Disease.” He also discussed it in phone interviews during which his mild cognitive impairment was barely noticeable.
In response to Gibbs’s criticism, Biogen said in a statement that “patient safety is our highest priority.” Less than 1 percent of patients who received the FDA’s recommended dosage in two trials that enrolled more than 3,200 volunteers “reported serious symptoms associated with ARIA,” the firm said. A 23-page FDA guide for prescribing the drug, which is intended for patients with mild cognitive impairment, recommends that doctors monitor for the potential side effect.
Dr. Sharon Cohen, a neurologist who runs the Toronto Memory Program and was a principal investigator in a late-stage trial of Biogen’s drug, says she has participated in studies of at least half a dozen other similar monoclonal antibodies that target amyloid. Almost all of them caused swelling and microhemorrhages in some patients, but those side effects rarely led to more serious symptoms.
“That doesn’t mean we trivialize it,” she said. “We monitor for it.”
Still, several doctors agreed that Aduhelm’s potential side effects, which also include headaches and falls, have received too little attention. Some are particularly concerned about patients like Gibbs who carry a gene known to dramatically heighten the chances of developing Alzheimer’s. That gene also substantially increases their chances of suffering microhemorrhages and brain swelling while taking Aduhelm, according to trial data, apparently because the drug binds to and breaks up more amyloid and moves fragments into the bloodstream.
About 25 percent of the population has one copy of the gene in question, APOE4, which doubles or triples the risk of developing Alzheimer’s, according to the National Institute on Aging. Gibbs is among the 2 or 3 percent of people with two copies, which increases the risk of developing the disease twelvefold.
All the participants in Biogen’s two large trials, including Gibbs, were genotyped beforehand to determine if they carried the gene. But when the FDA approved Aduhelm, regulators didn’t recommend that patients undergo genetic testing before receiving the drug, even though the agency acknowledged that the APOE4 gene heightens the possibility of side effects.
Dr. Lawren VandeVrede, a behavioral neurology clinical fellow at UCSF, said he would want to know whether a patient carries the gene before prescribing Aduhelm. That would help him and the patient to be vigilant about noticing side effects and to better weigh the risks and benefits of the drug, he said.
“Knowing your risk is important especially when balancing it against the relatively modest benefit ― maybe even questionably modest benefit ― of the drug,” he said. VandeVrede coauthored a paper about Gibbs’s case published last year in the journal Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring.
Dr. Susan Abushakra, a neurologist and chief medical officer at Alzheon, a Framingham biotech working on a rival Alzheimer’s drug that also targets amyloid, said she believes Aduhelm might help some patients. But she, too, says patients should undergo genotyping to learn if they carry the APOE4 gene.
“This is more than a nuisance headache,” she said, referring to Gibbs’s side effects. “He was in intensive care for several days.”
It took Gibbs almost a decade to learn for sure that he had Alzheimer’s, even though there had been clues since his mid-50s that concerned him because of his neurology expertise.
As he recounts in the book, which he wrote with veteran journalist Teresa H. Barker, the first hint came in 2006 when he and his wife, Lois Seed, were walking their dog. He leaned over to smell some roses and couldn’t detect a fragrance. About a year later, he started smelling a phantom odor that he described as a mixture of baking bread and perfume.
At first, Gibbs suspected he might have Parkinson’s disease because olfactory problems are a common early symptom. But in 2012 he and his wife, a genealogy enthusiast, took an at-home genetic test to learn more about their ancestry. A few weeks later, they received the online results. Gibbs was shocked to discover that he had two copies of the APOE4 gene.
“Alzheimer’s wasn’t on my radar screen at all because both of my parents died early from cancer,” said Gibbs, who noted that an impaired sense of smell can be a sign of Alzheimer’s.
About a year later, he began experiencing mild memory problems ― difficulty recalling a colleague’s name, trouble learning the phone number and address for his new office at Oregon Health & Science University, where he worked at the medical school. The impairment was so mild he would have ignored it had he not known the results of his genetic test.
Afraid he might make an error while treating patients, he decided to retire at age 62.
The definitive diagnosis came in 2015 when brain-imaging scans at UCSF revealed the unmistakable signs of Alzheimer’s, including a buildup of amyloid. The following year, Gibbs began participating in one of Biogen’s two late-stage trials of the drug, then called aducanumab, on the same campus. He was given a placebo by infusion for the first year and a half, then began getting the drug in the fall of 2017.
He received two monthly doses of 1 milligram per kilogram of his weight, then a third dose of 3 milligrams per kilogram. Soon afterward, Gibbs said, he started suffering headaches similar to his occasional migraines. Then he started having a hard time reading, and the crossword puzzles he enjoyed solving became as difficult as a Rubik’s Cube.
In retrospect, Gibbs said, he should have told trial researchers, but he was afraid they would withhold his next dose.
“That was just being stupid on my part,” he said. “I got the fourth dose of aducanumab, and it just poured gasoline on the fire.”
That’s when he ended up at the Portland hospital. An MRI showed brain swelling and microhemorrhages. Nurses gave him basic cognitive tests, but he was unable to name simple objects such as a feather and cactus.
Doctors soon got his blood pressure under control. But it took weeks after his discharge for him to regain the ability to read, balance a checkbook, and figure out a tip at a restaurant. Physicians gave him five daily infusions of high-dose steroids to reduce brain swelling. But the microhemorrhages left a residual iron pigment on his brain that is visible in MRI scans. Gibbs has likened it to a tattoo ― hence, the title of his book.
After recovering, Gibbs said, he actually felt sharper than he did before he took the Biogen drug. He wonders whether the medicine helped him despite the severe side effects. Or perhaps, he said, it’s because he started to take Aricept, an Alzheimer’s drug approved in 1996 that many neurologists say only modestly eases symptoms, if at all.
Gibbs was surprised the FDA approved Aduhelm on June 7, given the conflicting trial results. In one study, a high dose delayed cognitive decline by 22 percent. The other trial failed to prove the drug was effective. Like members of an independent advisory panel to the FDA that overwhelmingly voted in November that the agency shouldn’t approve the drug, he would have preferred that Biogen be directed to conduct a third trial.
But some neurologists are “of the opinion that we don’t have anything and maybe this will work for some people, and I don’t disagree with that,” Gibbs said. “It’s a difficult question.”
Jonathan Saltzman can be reached at firstname.lastname@example.org.