Amyloid-related imaging abnormalities, a concern for patients receiving aducanumab, were nearly all resolved during the 132-week period.
Newly announced long-term findings from the pivotal phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) studies and phase 1b PRIME study (NCT01677572) showed that treatment with aducanumab (Aduhelm; Biogen) 100 mg/mL injection significantly reduced amyloid-β plaque levels over 2 years of follow-up.1
Aducanumab, a monoclonal antibody directed against amyloid-β, was also associated with decreased plasma phosphorated tau 181 (p-tau 181) levels at 128 weeks. Individuals with greater amyloid-β clearance, indicated by standard uptake value ratio levels lower than 1.1 by 78 weeks, also demonstrated greater decreases in p-tau at week 128.
"These are meaningful findings, which further our understanding of amyloid and downstream biomarkers, such as p-tau 181, in Alzheimer’s disease and can help inform how long patients may benefit from treatment to reduce amyloid beta plaque," Samantha Budd Haeberliein, PhD, senior vice president, Head of Neurodegeneration Development, Biogen, said in a statement. "These data demonstrate that long-term treatment with Aduhelm continues to reduce the underlying pathologies of Alzheimer’s disease beyond two years."1
At week 78, patients with a reduction in plasma p-tau 181 demonstrated less clinical progression across the 4 clinical end points: Clinical Dementia Rating-Sum Box (CDR-SB), Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment (ADCS-ADL-MCI).
Aducanumab’s association with amyloid-related imaging abnormalities (ARIA) has been a point of concern throughout the life of the clinical program. In the placebo-controlled period of the phase 3 trials, the incidence of ARIA edema (ARIA-E) in the 10 mg/kg group was 35.2%. When including the long-term data, most ARIA-E events occurred prior to the 8th dose, or around the 96-week time point. Notably, 69% of cases were resolved within the first 12 weeks and 83% resolved within 16 weeks, and 98% of ARIA-E events were completely resolved within the 132-week extension period.
The incidence of ARIA was highest in apolipoprotein ε4 (APOE ε4) homozygous participants in EMERGE and ENGAGE. ARIA-E occurred in 66% (105 of 159) of APOE ε4 homozygous participants compared with 35.9% (185 of 515) heterozygous participants and 20.3% (72 of 355) of noncarriers. Similar differences were observed between groups for ARIA microhemorrhage or superficial siderosis. Notably, 18.2% of homozygous participants discontinued aducanumab due to ARIA, whereas only 5.0% and 2.5% of heterozygous and noncarriers stopped treatment.
EMERGE, ENGAGE, and PRIME were the basis for the original biologics license application submitted to the FDA in July 2020. In June 2021, the FDA approved the therapy under the Accelerated Approval pathway, marking it as the first ever disease-modifying therapy for the neurodegenerative disease and the first novel approval for AD since 2003. In its decision, the agency noted that the late-stage development program consisted of 2 pivotal trials, 1 which met its primary end point and 1 that did not.3
Those who received the agent in EMERGE reported a significant slowing of decline on measures of cognition and function such as memory, orientation, and language, as well as for activities of daily living. The trial ultimately hit its pre-specified end point, with high-dose aducanumab showing a statistically significant reduction of clinical decline from baseline in CDR-SB scores at 78 weeks (22% vs placebo; P = .01). Treatment with aducanumab was also associated with consistent reduction of clinical decline as measured by pre-specified secondary end points include the MMSE (18% vs placebo; P = .05), ADAS-Cog (27% vs placebo; P = .01), and ADCS-ADL-MCI (40% vs placebo; P = .001).4
Aducanumab’s controversial journey to approval began in March 2019, when Biogen announced it was discontinuing EMERGE and ENGAGE, along with a phase 2 safety study, EVOLVE (NCT03639987), following an interim futility analysis. However, in October 2019, the company had reversed course on their decision after conducting additional analyses, which found that the therapy was effective in patients who received the treatment at a higher dose and for a longer period of time.5,6 Later that year at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) annual meeting, December 4–7, 2019 in San Diego, California, new data from EMERGE and a post hoc analysis of a subset of patients who received high-dose treatment in ENGAGE were presented, suggesting that there were statistically significant changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, with P values of .010 or .031 based on cutoff dates. At that point, Biogen declared its intention to submit the agent to the FDA for review.7
In its review of aducanumab, the FDA noted that the data suggested the therapeutic "consistently and very convincingly" reduced amyloid plaques in both a dose- and time-dependent fashion. As part of the Accelerated Approval pathway, Biogen is required to conduct a phase 4 study to confirm the benefit of the drug. In December 2021, the company announced ICARE AD, a post-marketing study that is expected to have final protocol submitted this month, with plans to initiate patient screening in May 2022.8 In addition, Biogen is currently enrolling participants in the phase 3b EMBARK, (NCT04241068) who were actively participating in the clinical trial program when the PRIME, EVOLVE, EMERGE, and ENGAGE studies were terminated early in March 2019, and Biogen and Eisai recently announced details for its ENVISION study, another phase 4 trial of aducanumab that will include a more diverse study population.9
Although historic, the uptake of the drug into the treatment landscape has been challenging, as many groups raised concern regarding the drug’s cost and intended patient population. In December 2021, Biogen announced that it was halving the cost of the drug’s maintenance dose from $56,000 a year to $28,200. That news was followed by a proposed coverage decision from the Centers for Medicare and Medicaid Services (CMS), which said it will cover the administration of aducanumab for the treatment of AD only for those patients who are partaking in CMS-approved randomized controlled trials that satisfy its coverage criteria, and those in trials supported by the National Institutes of Health.