Diverse Enrollment, Primary End Point Announced for Phase 4 ENVISION Study of Aducanumab

Biogen and Eisai announced additional details regarding the phase 4 post-marketing confirmatory ENVISION study of aducanumab (Aduhelm) 100-mg/mL injection for the intravenous treatment of Alzheimer disease (AD) including a more diverse study population and the primary end point, which will measure patients’ cognitive decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) 18 months after treatment initiation with aducanumab.¹  

The study anticipates Black/African American and Latinx patients with AD to comprise 18% of the study population. The effort is in tandem with efforts to overcome barriers to enrollment in AD trials for these populations, including access to medical centers, familiarity with the risks and benefits of treatment, and financial or logistical burdens. 

Additionally, the target enrollment numbers for the ENVISION trial have also been increased from 1300 to 1500, including patients with AD (defined as mild cognitive impairment due to AD and mild AD), with confirmation of amyloid-ß pathology, which the companies expect to strengthen the data provided by the study. The trial is scheduled to commence patient screening in May 2022, with an anticipated completion date 4 years after the study begins. 

“Historically, patients from diverse backgrounds have been poorly represented in Alzheimer’s disease clinical trials, and we are committed to changing this,” Priya Singhal MD, MPH, head, Global Safety & Regulatory Sciences, and interim head, Research & Development, Biogen, said in a statement.¹ “This goal matches the diversity among Americans diagnosed with early Alzheimer’s disease, while at the same time, the trial will generate substantial data to verify the effectiveness of Aduhelm.”

“It’s important to see this ambitious focus on diversity being prioritized in enrollment and integrated as a key part of the ENVISION clinical trial, so that we can have data from patients who more closely represent what we see in the clinic,” Dylan Wint, MD, Cleveland Clinic Lou Ruvo Center for Brain Health, in Nevada, added in a statement.¹

The CDR-SB endpoint is consistent with the phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) studies of aducanumab, which were included as part of the supporting data for its accelerated approval. Secondary end points include the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13), Alzheimer’s Disease Cooperative Study-Activity of Daily Living Inventory-Mild Cognitive Impairment Version (ADCS-ALD-MCI), Integrated Alzheimer’s Disease Rating Scale (iADRS), Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI-10).

Earlier in January 2022, the Centers for Medicare and Medicaid Services (CMS) proposed the government’s health insurance program would cover the administration of aducanumab in the treatment of AD for patients partaking in the CMS-approved randomized controlled trials that satisfy its coverage criteria, and those in trials supported by the National Institutes of Health. Authored by a group including Joseph Chin, MD, MS, deputy director, Coverage and Analysis Group, and 6 others, the conclusion reached as it pertained to the clinical evidence of the monoclonal antibody (mAb) class was that “to date, no trial of an antiamyloid mAb has confidently demonstrated a clinically meaningful improvement in health outcomes (i.e., cognition and function) for AD patients. Thus, there is insufficient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Alzheimer’s disease under §1862(a)(1)(A) of the Social Security Act.” As it pertains to aducanumab specifically, the group wrote that the “available evidence is insufficient to establish that the treatment is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act.”² 

In December 2021, Biogen and Eisai announced an update on the status of the pending phase 4 study of aducanumab, ICARE AD (NCT05097131), noting that the final protocol for the post-marketing study would be submitted to the FDA in March 2022, with plans to initiate patient screening in May 2022.3 The study was originally announced during a late-breaking presentation at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30.

A separate announcement from the companies coming several days later confirmed that the companies were reducing the wholesale acquisition cost of the drug by 50.3%, from $56,000 yearly to $28,200 yearly for the maintenance dose (10 mg/kg) for individuals of an average weight (74 kg).⁴ This followed months of debate about the original pricing of the drug and its potential impact on both the federal and state level. Those conversations on pricing began immediately following the agent’s FDA approval, when, in early July, the Institute for Clinical and Economic Review (ICER) published an affirmation of its report on the cost from earlier in 2021, suggesting that in order for the agent to be cost-effective, its price would need to be between $2500-$8300 per patient per year. When calculating the price based on assumed "optimistic" treatment benefits—relying only on the results of the positive phase 3 study—ICER noted that pricing for the agent between $11,100-$23,100 would be needed for it to be considered cost-effective. Based on an assumption of "conservative" treatment benefits, the cost-effective range was reduced to between $1200 and $4200.⁵

REFERENCES
1. Update on the phase 4 ENVISION confirmatory study of Aduhelm. News release. Biogen. January 27, 2022. Accessed January 27, 2022. https://www.globenewswire.com/news-release/2022/01/27/2374228/0/en/Update-on-the-Phase-4-ENVISION-Confirmatory-Study-of-ADUHELM.html
2. Jensen TS, Chin J, Baldwin J, et al. Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. CMS website. January 11, 2022. Accessed January 27, 2022. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&ncaid=305&doctype=all&timeframe=30&sortBy=updated&bc=20
3. Update on the Phase 4 Confirmatory Study of ADUHELM®. Biogen. News release. December 16, 2021. Accessed January 27, 2022. https://investors.biogen.com/news-releases/news-release-details/update-phase-4-confirmatory-study-aduhelmr
4. Biogen Announces Reduced Price for ADUHELM® to Improve Access for Patients with Early Alzheimer’s Disease. Biogen. News release. December 20, 2021. Accessed January 22, 2022. https://www.globenewswire.com/news-release/2021/12/20/2355113/0/en/Biogen-Announces-Reduced-Price-for-ADUHELM-to-Improve-Access-for-Patients-with-Early-Alzheimer-s-Disease.html
5. Lin GA, Whittington MD, Synnott PG, McKenna A, Campbell J, Pearson SD, Rind DM. Aducanumab for Alzheimer’s Disease: Effectiveness and Value; Evidence Report. Institute for Clinical and Economic Review, June 30, 2021. Accessed January 27, 2022. https://icer.org/assessment/alzheimersdisease-2021/