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Much of the controversy surrounding the drug, called Aduhelm, has centered on conflicting test data as to whether it slows cognitive decline, its annual cost of $ 56,000, and the unusual process that led to its approval in June. But despite all the attention paid to the disputed benefits of Cambridge biotech firm medicine Gibbs says one important aspect of Aduhelm has been downplayed: its risks.
The drug reduces a sticky protein called amyloid that clumps together in plaques in the brains of people with Alzheimer’s disease. Some doctors believe that the buildup of amyloid causes cognitive impairment, although this is unproven and fiercely disputed. What is not in dispute is that about 40 percent of patients who received the highest dose in two late stage trials went on to experience abnormalities on MRI scans, irregularities indicating swelling in the brain. or tiny hemorrhages.
More than three-quarters of these “amyloid-related imaging abnormalities,” or ARIA, did not cause any 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 doctors can manage ARIA with MRI scans during treatment.
“I blame Biogen for despising ARIA,” said Gibbs, 70, who was hospitalized before reaching half the dosage of 10 milligrams per kilogram recommended by the Food and Drug Administration patients acquire. “I had a serious, potentially fatal, reaction to the medication. “
Doctors in Portland successfully treated Gibbs’ symptoms after consulting with researchers at the University of California San Francisco test site where he received monthly intravenous infusions. He doubts the side effects of Adulhelm will also be managed when doctors prescribe it in less tightly controlled environments. Biogen expects patients to receive infusions at 900 US clinics and hospitals.
“I would say that in the first year or so, the administration of the drug should be limited to [providers] with drug experience, “Gibbs said,” not just any guy with shingles. “
Gibbs vividly described his experience in a recently published book he wrote titled “A Tattoo on My Brain: A Neurologist’s Personal Battle with Alzheimer’s.” He also discussed it in phone interviews in which his mild cognitive impairment was barely noticeable.
Responding to Gibbs’ criticism, Biogen said in a statement that “patient safety is our top priority.” Less than 1% of patients who received the FDA recommended dose in two trials involving more than 3,200 volunteers “reported serious symptoms associated with ARIA,” the company said. A 23-page FDA guide to prescribing the drug, aimed at patients with mild cognitive impairment, recommends that doctors watch for potential side effects.
Dr. Sharon Cohen, a neurologist who runs the Toronto Memory Program and was a lead investigator in an advanced stage trial of Biogen’s drug, says she has been involved in studies of at least half a dozen other similar monoclonal antibodies that target amyloid. Almost all of them have caused swelling and microhemorrhages in some patients, but these side effects have rarely resulted in more severe symptoms.
“That doesn’t mean we trivialize it,” she said. “We are watching him. “
Still, several doctors have 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 increase the chances of developing Alzheimer’s disease. This gene also dramatically increases their chances of suffering from microhemorrhages and swelling of the brain while taking Aduhelm, according to trial data, apparently because the drug binds and breaks down more amyloid and moves fragments into the bloodstream. .
About 25 percent of the population has a copy of the gene in question, APOE4, which doubles or triples the risk of developing Alzheimer’s disease, according to the National Institute on Aging. Gibbs is among the 2-3 percent of people who have two copies, which increases the risk of developing the disease twelve-fold.
All participants in Biogen’s two large trials, including Gibbs, were pre-genotyped to determine if they carried the gene. But when the FDA approved Aduhelm, regulators did not recommend that patients undergo genetic testing before receiving the drug, even though the agency recognized that the APOE4 gene increases the possibility of side effects.
Dr Lawren VandeVrede, a behavioral neurology researcher at UCSF, said he would like to know if a patient has the gene before prescribing Aduhelm. It would help him and the patient to be vigilant to notice side effects and better weigh the risks and benefits of the drug, he said.
“Knowing your risk is important, especially when you compare it to the relatively modest benefit – perhaps even the modest questionable benefit – of the drug,” he said. VandeVrede is the co-author of an article on the Gibbs case published last year in the journal Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring.
Dr Susan Abushakra, 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 find out if they carry the APOE4 gene.
“It’s more than an annoying headache,” she said, referring to Gibbs’ side effects. “He was in intensive care for several days.
It took nearly a decade for Gibbs to know for sure that he had Alzheimer’s disease, even though there had been clues since his mid-50s that concerned him due to his expertise in neurology.
As he recounts in the book, which he wrote with veteran journalist Teresa H. Barker, the first clue came in 2006, when he and his wife, Lois Seed, were walking their dog. He bent down to smell roses and couldn’t detect a scent. About a year later, he started to smell a phantom odor which he described as a mixture of baking bread and perfume.
At first, Gibbs suspected he might have Parkinson’s disease because odor problems are a common early symptom. But in 2012, he and his wife, passionate about genealogy, took a genetic test at home to find out more about their ancestors. A few weeks later, they received the results online. Gibbs was shocked to discover he had two copies of the APOE4 gene.
“Alzheimer’s disease was not on my radar screen at all because both of my parents died prematurely of cancer,” said Gibbs, who noted that an altered sense of smell may be a sign of Alzheimer’s disease. ‘Alzheimer’s.
About a year later, he began to experience mild memory problems – difficulty remembering a colleague’s name, difficulty learning the phone number and the address of his new office at Oregon Health & Science University, where he worked in medical school. The impairment was so slight that he would have ignored he had not known the results of his genetic test.
Fearing he would make a mistake while treating patients, he decided to retire at 62.
The definitive diagnosis came in 2015 when brain imaging scans at UCSF revealed the unmistakable signs of Alzheimer’s disease, including amyloid buildup. 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 infusion for the first year and a half and then started taking the drug in the fall of 2017.
He received two monthly doses of 1 milligram per kilogram of his body weight, followed by a third dose of 3 milligrams per kilogram. Soon after, Gibbs said, he began to suffer from headaches similar to his occasional migraines. Then he started having trouble reading, and the crosswords he loved to solve became as difficult as a Rubik’s Cube.
In retrospect, Gibbs said, he should have told the trial researchers, but he feared they would withhold his next dose.
“It was just being stupid of me,” he said. “I got the fourth dose of aducanumab, and he just poured gasoline on the fire.
It was then that he ended up in the Portland hospital. An MRI showed swelling of the brain and microhemorrhages. Nurses gave him basic cognitive tests, but he was unable to name simple objects like a feather and a cactus.
Doctors quickly brought his blood pressure under control. But it took him weeks after his release to regain the ability to read, balance a checkbook, and find a tip at a restaurant. Doctors gave her five daily infusions of high-dose steroids to reduce brain edema. But the microhemorrhages left a residual iron pigment on his brain that is visible on MRI scans. Gibbs compared it to a tattoo hence the title of his book.
After he recovered, Gibbs said, he actually felt more alert than before taking the Biogen drug. He wonders if the drug has helped him despite the severe side effects. Or maybe, he said, it’s because he started taking Aricept, an Alzheimer’s drug approved in 1996 that many neurologists say only modestly relieves symptoms. if at all.
Gibbs was surprised that the FDA approved Aduhelm on June 7, given conflicting test results. In one study, a high dose delayed cognitive decline by 22%. The other trial failed to prove the drug was effective. Like members of an independent FDA advisory committee who voted overwhelmingly in November that the agency should not approve the drug, he would have preferred Biogen to be tasked with conducting a third trial.
But some neurologists are “of the opinion that we don’t have anything and maybe it will work for some people, and I don’t disagree with that,” Gibbs said. ” This is a difficult question.
Jonathan Saltzman can be reached at [email protected].
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