Q&A: Aduhelm 'should not be used' for off-label treatment of cerebral amyloid angiopathy

Aduhelm should not be used to treat cerebral amyloid angiopathy outside a clinical trial due to “substantial uncertainties and concerns” about the agent’s safety and efficacy, according to correspondence published in The Lancet Neurology.

“The FDA approved [Aduhelm] specifically for Alzheimer’s disease and noted in its prescribing information that ‘the safety of Aduhelm [aducanumab; Biogen/Eisai] in patients with any pre-treatment localized superficial siderosis, 10 or more brain microhemorrhages and/or with a brain hemorrhage greater than 1 cm within 1 year of treatment initiation has not been established,’” the authors wrote. “U.S. physicians will nevertheless be able to prescribe [Aduhelm] off label for the related condition of cerebral amyloid angiopathy.”

Healio Neurology spoke with Steven M. Greenberg, MD, PhD, director of the hemorrhagic stroke research program, vice chair of faculty development and promotions and John J. Conway Endowed Chair in Neurology at Massachusetts General Hospital and professor of neurology at Harvard Medical School, to learn more about the concerns raised in the correspondence. Greenberg coauthored the paper with other leaders of the International Cerebral Amyloid Angiopathy Association who are also “clinicians and investigators” in cerebral amyloid angiopathy (CAA).

Healio Neurology: What prompted this paper?

Greenberg: Patients diagnosed with CAA understand that their disease is caused by buildup of beta-amyloid in blood vessels. Many of them read about the FDA's approval of Aduhelm based on its ability to lower brain beta-amyloid and therefore began asking their doctors whether they should be treated with this medication. It is a very reasonable question, since CAA, like most other neurodegenerative-type diseases, does not yet have an established disease-modifying treatment. There is tremendous motivation to find such a treatment that would reduce the risk for CAA-related intracerebral hemorrhage or cognitive decline. My colleagues and I believe that Aduhelm is unfortunately not the answer, based on our current understanding of its efficacy and safety for CAA. We wrote our correspondence to The Lancet Neurology to state that it should not be used for this off-label indication and hope the correspondence will provide useful guidance to patients with CAA and their physicians in the United States and around the world.

Healio Neurology: How common is CAA and how is it currently treated?

Greenberg: CAA is a highly prevalent pathology of aging, appearing in a moderate-to-severe form in one-quarter to one-third of brains at autopsy. It therefore appears to be a very common contributor to age-related cognitive impairment. CAA-related hemorrhagic strokes are less common, on the order of approximately 20,000 in the United States per year, but — like other hemorrhagic strokes — have very high morbidity and mortality. Current treatment is focused on reducing bleeding risk by avoiding antithrombotic medications where there is not sufficient counterbalancing benefit, monitoring and controlling blood pressure, and counseling on other lifestyle issues such as avoiding heavy alcohol use.

Healio Neurology: Can you elaborate on your concerns related to efficacy and safety?

Greenberg: Based on our review of the evidence, my coauthors and I felt that Aduhelm has not shown benefit for CAA and raises substantial safety concerns. On the efficacy side, we noted that vascular beta-amyloid deposits appear more difficult to clear with anti-amyloid immunotherapy than brain parenchymal beta-amyloid deposits and may actually be worsened by mobilizing plaque amyloid into the perivascular spaces. One short-term, 3-month immunotherapy trial of a different anti-amyloid antibody for CAA indeed showed a trend toward worsened rather than improved vessel function. On the safety side, we noted that CAA appears to be an important trigger for the amyloid-related imaging abnormalities (ARIA) that are the major adverse effects associated with Aduhelm and other anti-amyloid immunotherapies. ARIA occurred commonly in the trials of Aduhelm and would be expected to occur even more commonly in patients with CAA.

Healio Neurology: Do you think further action is needed to discourage this off-label use?

Greenberg: We hope our correspondence will help publicize the efficacy and safety concerns regarding off-label use of Aduhelm for the treatment of CAA. We believe sharing our thought process with the medical community is the most effective step for discouraging its off-label use.

Healio Neurology: What research is needed to improve the treatment of CAA?

Greenberg: There are many mechanistic targets and rational scientific approaches to slowing or stopping the course of CAA. Immunotherapy remains a viable treatment possibility, along with other approaches such as reducing amyloid production, enhancing amyloid clearance, preventing vascular deposition and protecting small vessel structure and function. Identifying disease-modifying treatments is obviously a challenge for all of us, but we are very optimistic about the future of CAA treatment.

Reference:

Greenberg SM, et al. Lancet Neurol. 2021;doi:10.1016/S1474-4422(21)00213-1.