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A novel therapy recently approved by the U.S. Food and Drug Administration for patients with Alzheimer disease amid considerable controversy should not be prescribed by physicians off-label for cerebral amyloid angiopathy, a similar cerebrovascular condition, according to Steven Greenberg MD PhD, director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital (MGH) and president of the International Cerebral Amyloid Angiopathy Association (ICAAA). In a letter published in The Lancet Neurology, Greenberg and 8 other officers of the association wrote that there is no clinical evidence that the monoclonal antibody aducanumab is beneficial to patients with cerebral amyloid angiopathy, a condition in which proteins known as amyloid corrode arterial walls in the brain and can lead to bleeding and stroke.
"We believe that there are substantial uncertainties and concerns about both the safety and efficacy of aducanumab in patients diagnosed with cerebral amyloid angiopathy [and] therefore believe [it] should not be used for the purpose of treating cerebral amyloid angiopathy outside the context of a research trial," the letter stated.
The FDA approved aducanumab on June 7 under the FDA's accelerated approval process for drugs that treat serious conditions and fill an unmet medical need. While the approval was specifically for Alzheimer disease, it opens the door for physicians to legally prescribe aducanumab off-label for cerebral amyloid angiopathy. Indeed, cerebral amyloid angiopathy is thought to be triggered, as in Alzheimer disease, by a harmful accumulation of amyloid beta deposits in the brain. Unlike Alzheimer disease, however, those deposits typically gather in the cerebral blood vessels, not the brain tissue itself. In giving the green light to aducanumab, the FDA took a position contrary to its own independent advisory committee, as well as many scientists and physicians, who contend there is no convincing evidence to show the drug helps patients.
Leading authorities in the field of cerebral amyloid angiopathy have now taken their own stand, recommending that aducanumab not be prescribed off-label for treatment of cerebral amyloid angiopathy. From an efficacy standpoint, the ICAAA officers noted that amyloid beta deposits in blood vessels of the brain appear to be more resistant to antibody-mediated treatment than plaque deposits in the brain tissue, and that insufficient evidence existed to suggest aducanumab was capable of clearing those blood vessels. The physicians cited a previous clinical trial of another anti-amyloid antibody, ponezumab, which found that blood vessel function in patients with cerebral amyloid angiopathy trended toward worsening rather than improving following 3 monthly infusions of the agent.
In terms of safety, the letter from Greenberg and his colleagues cited the fact that amyloid-related imaging abnormalities (ARIAs) had emerged as major adverse events in patients enrolled in trials of aducanumab and other anti-amyloid antibody drugs. ARIAs, which manifest as bleeding or swelling in the brain and are detectable through MRI imaging, are postulated to be triggered by cerebral amyloid angiopathy. What the physicians found worrisome was that these abnormalities might occur even more frequently in patients being treated for cerebral amyloid angiopathy than the high rates observed in patients treated for Alzheimer disease.
While discouraging off-label use of aducanumab, Greenberg drew a distinction between patients diagnosed with cerebral amyloid angiopathy and those diagnosed with Alzheimer disease. "We haven't taken a position on whether an Alzheimer disease patient who also has markers of cerebral amyloid angiopathy should be prescribed aducanumab," he says. "What we are saying is that the drug shouldn't be prescribed for the purpose of treating cerebral amyloid angiopathy."
Source: News Release
Massachusetts General Hospital
July 6, 2021