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.
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
ENVISION’s primary end point, which was
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
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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
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."
REFERENCES
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. https://www.biospace.com/article/releases/biogen-submits-final-protocol-for-aduhelm-aducanumab-avwa-phase-4-envision-trial-to-fda/
2. Update on the phase 4 ENVISION confirmatory study of Aduhelm. News release. Biogen. January 27, 2022. Accessed March 30, 2022. https://www.globenewswire.com/news-release/2022/01/27/2374228/0/en/Update-on-the-Phase-4-ENVISION-Confirmatory-Study-of-ADUHELM.html
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. https://www.biospace.com/article/releases/long-term-phase-3-data-show-aduhelm-continues-to-reduce-underlying-pathologies-of-alzheimer-s-disease-in-patients-treated-for-more-than-two-years/
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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