Daniel Gibbs had obtained 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 docs thought he may 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 unintended effects of the drug. Docs prescribed medicines to decrease his blood strain, which reached 206/116, and later to cut back mind swelling. However for weeks afterward, he struggled to learn, observe conversations, and do simple arithmetic. He recovered however by no means once more took the Alzheimer’s drug.
A lot of the controversy surrounding the remedy, known as Aduhelm, has centered on conflicting trial information 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 targeted on the disputed advantages of the Cambridge biotechnology agency’s drugs, Gibbs says an vital facet of Aduhelm has been downplayed ― its dangers.
The drug reduces a sticky protein known as amyloid that clumps into plaques within the brains of individuals with Alzheimer’s. Some docs imagine amyloid buildup causes cognitive impairment, though that’s unproven and fiercely contested. What’s not in dispute is that this: About 40 % of sufferers who obtained the very 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 % of sufferers on the very best dose needed to cease taking the drug. Biogen acknowledges that swelling specifically is widespread, however says it often goes away by itself and that docs 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 docs efficiently handled Gibbs’s signs after consulting with researchers on the College of California San Francisco trial website the place he obtained month-to-month intravenous infusions. He doubts Aduhelm’s unintended effects can be managed as properly when docs 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 yr 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 not too long ago revealed e book he wrote known as “A Tattoo on My Mind: A Neurologist’s Private Battle In opposition to Alzheimer’s Illness.” He additionally mentioned it in telephone interviews throughout which his gentle 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 % of sufferers who obtained the FDA’s advisable 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 gentle cognitive impairment, recommends that docs monitor for the potential facet 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 related monoclonal antibodies that focus on amyloid. Nearly all of them triggered swelling and microhemorrhages in some sufferers, however these unintended effects hardly ever led to extra critical signs.
“That doesn’t imply we trivialize it,” she stated. “We monitor for it.”
Nonetheless, a number of docs agreed that Aduhelm’s potential unintended effects, which additionally embody complications and falls, have obtained too little consideration. Some are significantly involved about sufferers like Gibbs who carry a gene identified to dramatically heighten the possibilities of growing Alzheimer’s. That gene additionally considerably will increase their possibilities of struggling microhemorrhages and mind swelling whereas taking Aduhelm, based on trial information, apparently as a result of the drug binds to and breaks up extra amyloid and strikes fragments into the bloodstream.
About 25 % of the inhabitants has one copy of the gene in query, APOE4, which doubles or triples the chance of growing Alzheimer’s, based on the Nationwide Institute on Growing older. Gibbs is among the many 2 or 3 % of individuals with two copies, which will increase the chance of growing the illness twelvefold.
All of the members in Biogen’s two giant trials, together with Gibbs, have been genotyped beforehand to find out in the event that they carried the gene. However when the FDA authorised Aduhelm, regulators didn’t advocate that sufferers endure genetic testing earlier than receiving the drug, although the company acknowledged that the APOE4 gene heightens the potential for unintended effects.
Dr. Lawren VandeVrede, a behavioral neurology medical fellow at UCSF, stated he would need to know whether or not a affected person carries the gene earlier than prescribing Aduhelm. That may assist him and the affected person to be vigilant about noticing unintended effects and to higher weigh the dangers and advantages of the drug, he stated.
“Understanding your threat is vital particularly when balancing it towards the comparatively modest profit ― possibly even questionably modest profit ― of the drug,” he stated. VandeVrede coauthored a paper about Gibbs’s case revealed final yr within the journal Alzheimer’s & Dementia: Prognosis, 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 endure 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 unintended effects. “He was in intensive look after a number of days.”
It took Gibbs virtually a decade to study for certain that he had Alzheimer’s, although 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, have been strolling their canine. He leaned over to scent some roses and couldn’t detect a perfume. A few yr later, he began smelling a phantom odor that he described as a mix of baking bread and fragrance.
At first, Gibbs suspected he might need Parkinson’s illness as a result of olfactory issues are a typical 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. A number of weeks later, they obtained the net outcomes. Gibbs was shocked to find that he had two copies of the APOE4 gene.
“Alzheimer’s wasn’t on my radar display in any respect as a result of each of my dad and mom died early from most cancers,” stated Gibbs, who famous that an impaired sense of scent generally is a signal of Alzheimer’s.
A few yr later, he started experiencing gentle reminiscence issues ― issue recalling a colleague’s identify, bother studying the telephone quantity and tackle for his new workplace at Oregon Well being & Science College, the place he labored on the medical college. The impairment was so gentle he would have ignored it had he not identified 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 yr, Gibbs started collaborating in one in all Biogen’s two late-stage trials of the drug, then known as aducanumab, on the identical campus. He was given a placebo by infusion for the primary yr and a half, then started getting the drug within the fall of 2017.
He obtained 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 just like his occasional migraines. Then he began having a tough time studying, and the crossword puzzles he loved fixing turned as troublesome as a Rubik’s Dice.
Looking back, 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 checks, however he was unable to call easy objects reminiscent of a feather and cactus.
Docs quickly received his blood strain underneath management. Nevertheless it took weeks after his discharge for him to regain the flexibility to learn, stability a checkbook, and work out a tip at a restaurant. Physicians gave him 5 day by day infusions of high-dose steroids to cut 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 drugs helped him regardless of the extreme unintended 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 shocked the FDA authorised Aduhelm on June 7, given the conflicting trial outcomes. In a single examine, a excessive dose delayed cognitive decline by 22 %. The opposite trial did not 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 possibly it will work for some individuals, and I don’t disagree with that,” Gibbs stated. “It’s a troublesome query.”