Daniel Gibbs had acquired solely 4 month-to-month doses of Biogen’s experimental Alzheimer’s drug in a medical trial in 2017 when he ended up in an intensive care unit. He had an excruciating headache, and his blood strain was so excessive that medical doctors thought he could be having a stroke.
It turned out that the retired Portland, Ore., neurologist ― who had handled Alzheimer’s sufferers earlier than he was recognized with the illness himself in 2015 ― was experiencing a number of the worst reported negative effects of the drug. Docs prescribed medicines to decrease his blood strain, which reached 206/116, and later to scale back mind swelling. However for weeks afterward, he struggled to learn, observe conversations, and do basic math. He recovered however by no means once more took the Alzheimer’s drug.
A lot of the controversy surrounding the treatment, referred to as Aduhelm, has centered on conflicting trial knowledge about whether or not it slows cognitive decline, its $56,000 annual value, and the weird course of that led to its June approval. However for all the eye centered on the disputed advantages of the Cambridge biotechnology agency’s drugs, Gibbs says an necessary side of Aduhelm has been downplayed ― its dangers.
The drug reduces a sticky protein referred to as amyloid that clumps into plaques within the brains of individuals with Alzheimer’s. Some medical doctors imagine amyloid buildup causes cognitive impairment, though that’s unproven and fiercely contested. What’s not in dispute is that this: About 40 p.c of sufferers who acquired the best dose in two late-stage trials later confirmed abnormalities on MRI scans, irregularities that indicated mind swelling or tiny hemorrhages.
Greater than three-quarters of these “amyloid-related imaging abnormalities,” or ARIA, triggered no signs. However about 6 p.c of sufferers on the best dose needed to cease taking the drug. Biogen acknowledges that swelling particularly is widespread, however says it often goes away by itself and that medical doctors can handle ARIA with MRI scans throughout remedy.
“I fault Biogen for being dismissive in regards to the ARIA,” stated Gibbs, 70, who was hospitalized earlier than he received midway to the dosage of 10 milligrams per kilogram that the Meals and Drug Administration recommends sufferers construct as much as. “I had a extreme, doubtlessly life-threatening response to the drug.”
Portland medical doctors efficiently handled Gibbs’s signs after consulting with researchers on the College of California San Francisco trial website the place he acquired month-to-month intravenous infusions. He doubts Aduhelm’s negative effects can be managed as properly when medical doctors prescribe it in much less tightly managed settings. Biogen expects sufferers will obtain infusions at 900 US clinics and hospitals.
“I’d argue that within the first 12 months or so, administration of the drug needs to be restricted to [providers] with expertise with the drug,” Gibbs stated, “not simply any man with a shingle.”
Gibbs vividly described his expertise in a lately printed e book he wrote referred to as “A Tattoo on My Mind: A Neurologist’s Private Battle Towards Alzheimer’s Illness.” He additionally mentioned it in cellphone interviews throughout which his delicate cognitive impairment was barely noticeable.
In response to Gibbs’s criticism, Biogen stated in an announcement that “affected person security is our highest precedence.” Lower than 1 p.c of sufferers who acquired the FDA’s really helpful dosage in two trials that enrolled greater than 3,200 volunteers “reported critical signs related to ARIA,” the agency stated. A 23-page FDA information for prescribing the drug, which is meant for sufferers with delicate cognitive impairment, recommends that medical doctors monitor for the potential aspect impact.
Dr. Sharon Cohen, a neurologist who runs the Toronto Reminiscence Program and was a principal investigator in a late-stage trial of Biogen’s drug, says she has participated in research of a minimum of half a dozen different comparable monoclonal antibodies that focus on amyloid. Nearly all of them triggered swelling and microhemorrhages in some sufferers, however these negative effects not often led to extra critical signs.
“That doesn’t imply we trivialize it,” she stated. “We monitor for it.”
Nonetheless, a number of medical doctors agreed that Aduhelm’s potential negative effects, which additionally embrace complications and falls, have acquired too little consideration. Some are significantly involved about sufferers like Gibbs who carry a gene recognized to dramatically heighten the possibilities of creating Alzheimer’s. That gene additionally considerably will increase their possibilities of struggling microhemorrhages and mind swelling whereas taking Aduhelm, in response to trial knowledge, apparently as a result of the drug binds to and breaks up extra amyloid and strikes fragments into the bloodstream.
About 25 p.c of the inhabitants has one copy of the gene in query, APOE4, which doubles or triples the danger of creating Alzheimer’s, in response to the Nationwide Institute on Getting old. Gibbs is among the many 2 or 3 p.c of individuals with two copies, which will increase the danger of creating the illness twelvefold.
All of the individuals in Biogen’s two massive trials, together with Gibbs, had been genotyped beforehand to find out in the event that they carried the gene. However when the FDA authorised Aduhelm, regulators didn’t suggest that sufferers bear genetic testing earlier than receiving the drug, despite the fact that the company acknowledged that the APOE4 gene heightens the opportunity of negative effects.
Dr. Lawren VandeVrede, a behavioral neurology medical fellow at UCSF, stated he would wish to know whether or not a affected person carries the gene earlier than prescribing Aduhelm. That will assist him and the affected person to be vigilant about noticing negative effects and to raised weigh the dangers and advantages of the drug, he stated.
“Realizing your danger is necessary particularly when balancing it in opposition to the comparatively modest profit ― perhaps even questionably modest profit ― of the drug,” he stated. VandeVrede coauthored a paper about Gibbs’s case printed final 12 months within the journal Alzheimer’s & Dementia: Analysis, Evaluation & Illness Monitoring.
Dr. Susan Abushakra, a neurologist and chief medical officer at Alzheon, a Framingham biotech engaged on a rival Alzheimer’s drug that additionally targets amyloid, stated she believes Aduhelm may assist some sufferers. However she, too, says sufferers ought to bear genotyping to study in the event that they carry the APOE4 gene.
“That is greater than a nuisance headache,” she stated, referring to Gibbs’s negative effects. “He was in intensive look after a number of days.”
It took Gibbs nearly a decade to study for positive that he had Alzheimer’s, despite the fact that there had been clues since his mid-50s that involved him due to his neurology experience.
As he recounts within the e book, which he wrote with veteran journalist Teresa H. Barker, the primary trace got here in 2006 when he and his spouse, Lois Seed, had been strolling their canine. He leaned over to scent some roses and couldn’t detect a perfume. A few 12 months later, he began smelling a phantom odor that he described as a mix of baking bread and fragrance.
At first, Gibbs suspected he may need Parkinson’s illness as a result of olfactory issues are a standard early symptom. However in 2012 he and his spouse, a family tree fanatic, took an at-home genetic check to study extra about their ancestry. Just a few weeks later, they acquired the web outcomes. Gibbs was shocked to find that he had two copies of the APOE4 gene.
“Alzheimer’s wasn’t on my radar display screen in any respect as a result of each of my mother and father died early from most cancers,” stated Gibbs, who famous that an impaired sense of scent is usually a signal of Alzheimer’s.
A few 12 months later, he started experiencing delicate reminiscence issues ― problem recalling a colleague’s title, hassle studying the cellphone quantity and deal with for his new workplace at Oregon Well being & Science College, the place he labored on the medical college. The impairment was so delicate he would have ignored it had he not recognized the outcomes of his genetic check.
Afraid he may make an error whereas treating sufferers, he determined to retire at age 62.
The definitive prognosis got here in 2015 when brain-imaging scans at UCSF revealed the unmistakable indicators of Alzheimer’s, together with a buildup of amyloid. The next 12 months, Gibbs started collaborating in one in every of Biogen’s two late-stage trials of the drug, then referred to as aducanumab, on the identical campus. He was given a placebo by infusion for the primary 12 months and a half, then started getting the drug within the fall of 2017.
He acquired two month-to-month doses of 1 milligram per kilogram of his weight, then a 3rd dose of three milligrams per kilogram. Quickly afterward, Gibbs stated, he began struggling complications much like his occasional migraines. Then he began having a tough time studying, and the crossword puzzles he loved fixing grew to become as tough as a Rubik’s Dice.
On reflection, Gibbs stated, he ought to have advised trial researchers, however he was afraid they’d withhold his subsequent dose.
“That was simply being silly on my half,” he stated. “I received the fourth dose of aducanumab, and it simply poured gasoline on the hearth.”
That’s when he ended up on the Portland hospital. An MRI confirmed mind swelling and microhemorrhages. Nurses gave him primary cognitive assessments, however he was unable to call easy objects reminiscent of a feather and cactus.
Docs quickly received his blood strain below management. Nevertheless it took weeks after his discharge for him to regain the flexibility to learn, steadiness a checkbook, and work out a tip at a restaurant. Physicians gave him 5 each day infusions of high-dose steroids to scale back mind swelling. However the microhemorrhages left a residual iron pigment on his mind that’s seen in MRI scans. Gibbs has likened it to a tattoo ― therefore, the title of his e book.
After recovering, Gibbs stated, he truly felt sharper than he did earlier than he took the Biogen drug. He wonders whether or not the medication helped him regardless of the extreme negative effects. Or maybe, he stated, it’s as a result of he began to take Aricept, an Alzheimer’s drug authorised in 1996 that many neurologists say solely modestly eases signs, if in any respect.
Gibbs was stunned the FDA authorised Aduhelm on June 7, given the conflicting trial outcomes. In a single examine, a excessive dose delayed cognitive decline by 22 p.c. The opposite trial didn’t show the drug was efficient. Like members of an impartial advisory panel to the FDA that overwhelmingly voted in November that the company shouldn’t approve the drug, he would have most well-liked that Biogen be directed to conduct a 3rd trial.
However some neurologists are “of the opinion that we don’t have something and perhaps this can work for some individuals, and I don’t disagree with that,” Gibbs stated. “It’s a tough query.”