Many people on aducanumab (trade name Aduhelm) develop the amyloid-related imaging abnormalities (ARIA) that mark fluid retention and microhemorrhages in the brain. In the November 22 JAMA Neurology, researchers led by Stephen Salloway at Brown University in Providence, Rhode Island, formally published the incidence and severity data from the aducanumab Phase 3 EMERGE and ENGAGE trials.
- Overall, about one-third of people taking Aduhelm developed ARIA-E.
- Of these, a quarter were symptomatic, 3 percent were serious.
- Having brain microhemorrhage at baseline, or APOE4, increased risk.
Overall, 41 percent of people taking the highest dose developed ARIA, compared to 10 percent of controls. Most cases were asymptomatic, and most symptoms were mild. However, 1 percent of participants experienced serious side effects, i.e., those requiring hospitalization or causing long-lasting impairment. Some of these data were previously reported at the 2021 Alzheimer’s Association International Conference (Aug 2021 conference news).
Adam Brickman at Columbia University, New York City, cautioned that the ARIA profile might be worse in clinical practice, where a broader range of patients are likely to be treated and monitoring may be less stringent. Brickman believes the trials’ lack of diversity leaves unclear how the results would generalize to a typical clinic population.
Others have expressed similar concerns, with one recent study noting that 92 percent of Medicare patients would not have qualified for the Phase 3 trials due to comorbidities such as cerebrovascular disease and other exclusions (Oct 2021 news). Additional reports of adverse events and a death potentially linked to aducanumab have surfaced (Nov 2021 conference news).
In these two Phase 3 studies, the incidence of ARIA rose with dose. At 10 mg/kg—the dosage approved for clinical use—35 percent of participants developed the edema known as ARIA-E. This compared to an incidence of 2.7 percent on placebo. Notably, ARIA-E sometimes popped up in the same person more than once, with 10 percent of the high-dose group having recurrent episodes.
About 40 percent of people with ARIA-E also had the microhemorrhages known as ARIA-H. ARIA-H without ARIA-E was less frequent, at about 8 percent of the cohort, which was similar to the control group. About 6 percent of the high-dose cohort discontinued treatment due to ARIA-E or -H.
Three-quarters of all ARIA cases were asymptomatic and detected only on MRI. Of the symptomatic cases, two-thirds were mild, with the most common symptoms being headache, confusion, dizziness, and nausea. Most cases resolved within 16 weeks.
Factors such as age, sex, disease stage, or use of blood thinners did not affect ARIA-E incidence in these trials. In contrast, the presence of microhemorrhages at study baseline nearly doubled a person’s risk. APOE genotype likewise had a large effect, with ARIA-E incidence being 20 percent in noncarriers, 36 percent in heterozygotes, and 66 percent in homozygotes. For ARIA-H risk, APOE status and baseline microhemorrhages had no effect, but older age did.
As have others, Brickman bemoaned the fact that the efficacy data remain unpublished 2.5 years after the two trials were halted. “Scientists … should have the opportunity to scrutinize both the efficacy and the safety data not only in the form of peer-reviewed publications, but also via access to the raw data for re-analysis. An important question with respect to the newly reported findings is whether ARIA or baseline cerebrovascular status moderates clinical efficacy,” Brickman wrote.
Separately, Brickman wondered whether ARIA might ultimately hasten cognitive decline. “It’s hard to put a positive spin on the neuroimaging abnormalities … we simply do not know the long-term consequences,” he wrote to Alzforum (full comment below).
Meanwhile, in Washington, D.C., the Centers for Medicare and Medicaid Services is deliberating whether to cover Aduhelm, or go for a coverage with evidence development program. On December 10, Senator Ron Wyden (D-OR), called on Department of Health and Human Services Secretary Xavier Becerra to hold off on a scheduled 2022 increase in Medicare premiums for the country’s elderly population until after the CMS has rendered its decision, which is expected to come around January 12 (Wyden letter to HHS). When Medicare rejects coverage of an FDA-approved drug, state Medicaid programs pick up the cost; alas, resistance seems to be forming among some state Medicaid directors. Today, Stat reported that Oregon is preparing a request to be released from this requirement.
On December 3 in Science magazine, Holly Fernandez Lynch, University of Pennsylvania, and Christopher Robertson, Boston University, joined a growing chorus of researchers demanding that accelerated approval be buttressed with better, faster confirmatory trials (Lynch and Robertson, 2021).—Madolyn Bowman Rogers
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- Lynch HF, Robertson CT. Challenges in confirming drug effectiveness after early approval. Science. 2021 Dec 3;374(6572):1205-1207. Epub 2021 Dec 2 PubMed.
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- Salloway S, Chalkias S, Barkhof F, Burkett P, Barakos J, Purcell D, Suhy J, Forrestal F, Tian Y, Umans K, Wang G, Singhal P, Budd Haeberlein S, Smirnakis K. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol. 2022 Jan 1;79(1):13-21. PubMed.