Biogen Submits Aducanumab’s Phase 4 ENVISION Trial Protocol to FDA


The company anticipates the first patient to be screened in May 2022, with a primary end point of cognitive decline at 18 months, measured by the Clinical Dementia Rating-Sum of Boxes.

Samantha Budd Haeberliein, PhD

Samantha Budd Haeberliein, PhD

Biogen has submitted the final study protocol to the FDA for the phase 4 ENVISION trial of aducanumab (Aduhelm) to be reviewed by the agency. The company noted in an announcement that it anticipates the first patient to be screened in May 2022.1

The trial will be conducted as part of the accelerated approval of aducanumab in June 2021, and will be global in scale, with a targeted enrollment of 1500 patients with Alzheimer disease (AD) and confirmed amyloid-ß pathology. The 100 mg/mL injection was approved for intravenous infusion in early AD, including those with mild cognitive impairment (MCI) because of AD and mild AD.

ENVISION’s primary end point, which was originally detailed in an announcement from January 2022,2 will be cognitive decline at 18 months, measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Additionally, a long-term extension is planned to collect data for up to 48 months.

The trial’s secondary end points include change in amyloid PET and tau PET, as well as scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13), Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory–Mild Cognitive Impairment Version (ADCS-ADL-MCI), Integrated Alzheimer's Disease Rating Scale (iADRS), Mini-Mental State Examination (MMSE), and Neuropsychiatric Inventory (NPI-10). The original supporting trials included the CDR-SB, MMSE, ADAS-Cog, and the ADCS-ADL-MCI.

“Our unwavering commitment is to ensure that the trial is completed swiftly and that the diversity of patients in it reflects that of Americans diagnosed with early Alzheimer’s disease. We plan to work hand-in-hand with underrepresented communities and Alzheimer’s disease groups to achieve our diversity and inclusion goal,” Samantha Budd Haeberlein, PhD, senior vice president and head of Neurodegeneration Development, Biogen, said in a statement.1

READ MORE: FDA Clears IND for Antiamyloid Antibody for Alzheimer Disease, Set to Initiate Trial

Echoing Budd Haeberlein’s statement, Biogen noted it is still aiming to reach an 18% enrollment of patients from Black/African American and Latino communities. To do so, the company stated that it is “leveraging multiple initiatives and working with several community groups, such as the National Minority Quality Forum and others who have expertise and a commitment in helping to overcome traditional enrollment barriers for diverse populations.” Specifically, Biogen noted it plans to select trial sites that feature diverse staff and that are in communities of color with access to diverse patient populations. Additionally, it will seek to support trial sites with the identification, outreach, and engagement of underrepresented communities, and work with community and patient organizations.

This announcement for ENVISION comes just a few weeks after Biogen announced long-term data from the supporting pivotal phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) studies, as well as phase 1b PRIME study (NCT01677572).3 Those findings suggested that treatment with aducanumab significantly reduced amyloid-β plaque levels over 2 years of follow-up. The monoclonal antibody 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. At week 78, patients with a reduction in plasma p-tau 181 demonstrated less clinical progression across the 4 clinical end points.3,4

Additonally, aducanumab has been association with amyloid-related imaging abnormalities (ARIA), a noted point concern from the clinical community. 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 eighth dose, roughly the 96-week time point. In total, 69% of cases were resolved in the first 12 weeks and 83% resolved within 16 weeks, while 98% of ARIA-E events were completely resolved within the 132-week extension period.

In the phase 3 trials, ARIA incidence was highest in apolipoprotein ε4 (APOE ε4) homozygous participants. 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.

In mid-March, Budd Haeberliein called the long-term findings “meaningful” in a statement,3 adding that they “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."

1. Biogen Submits Final Protocol for ADUHELM® (aducanumab-avwa) Phase 4 ENVISION Trial to FDA. News release. Biogen. March 30, 2022. Accessed March 30, 2022.
2. Update on the phase 4 ENVISION confirmatory study of Aduhelm. News release. Biogen. January 27, 2022. Accessed March 30, 2022.
3. Long-term phase 3 data show aduhelm continues to reduce underlying pathologies of Alzheimer disease in patients treated for more than 2 years. News release. Biogen. March 16, 2022. Accessed March 30, 2022.
4. Haeberlein S. Key milestones in Alzheimer’s disease. Presented at 2022 AD/PD International Conference; March 15-20, 2022; Barcelona, Spain.
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