What is the clinical evidence supporting, and controversy surrounding, the use of aducanumab (Aduhelm TM) for Alzheimer disease?

Introduction
On June 7, 2021, the United States Food and Drug Administration (FDA) approved aducanumab, (AduhelmÔ; Biogen) for the treatment of Alzheimer disease (AD).^1,2 While aducanumab was originally approved for the treatment of all patients with AD, the labeling was later revised to specify that the medication should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, as studied in clinical trials.³ Aducanumab was approved through the accelerated approval pathway of the FDA based on clinical evidence demonstrating a reduction of amyloid beta plaques in the brain.^1-3 The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of AD.¹ Aducanumab is an amyloid beta-directed monoclonal antibody, and it is the first and only AD treatment to address a defining disease pathology.^1,2,4 Aducanumab is also the first AD treatment approved by the FDA since 2003, further increasing the excitement regarding the drug.²

According to the prescribing information, aducanumab is administered as an intravenous infusion every 4 weeks, and the recommended dosage is 10 mg/kg after an initial titration.⁴ The dosing titration schedule for aducanumab is summarized in Table 1. Warnings and precautions for aducanumab include hypersensitivity reactions, specifically angioedema and urticaria, and amyloid-related imaging abnormalities (ARIA). Amyloid-related imaging abnormalities include both ARIA-edema (ARIA-E) and ARIA-hemosiderin deposition (ARIA-H); ARIA-E is seen as brain edema or sulcal effusions on magnetic resonance imaging (MRI) scans, and ARIA-H includes microhemorrhage and superficial siderosis. Therefore, clinicians must obtain an MRI before initiating treatment (within 1 year) and prior to the 7th (1st dose of 10 mg/kg), and 12th infusions (6th dose of 10 mg/kg). The most common adverse reactions reported with aducanumab are ARIA-E, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and falls.

Clinical trials for aducanumab   
Biogen sponsored several clinical trials involving aducanumab.⁵ Four phase 1 trials were undertaken and assessed aducanumab in healthy volunteers (NCT02782975), mild to moderate AD patients in Japan (NCT02434718; PROPEL), mild to moderate AD patients in the United States (NCT01397539), and prodromal or mild AD patients in the United States (NCT01677572; PRIME).^5-9 The PRIME trial was a randomized, double-blind, placebo-controlled study conducted at 32 sites that was eventually discontinued based on a futility analysis of data from phase 3 trials.^5,9 The primary objective of the study was to evaluate the safety and tolerability of multiple doses of aducanumab. Clinical endpoints included changes in amyloid plaques (measured with positron emission tomography imaging) and measures of clinical decline, assessed as changes in the clinical dementia rating sum of boxes (CDR-SB) and the mini-mental state examination (MMSE).⁵ The trial enrolled 192 patients, and interim results from the first 165 patients demonstrated that all doses of aducanumab significantly reduced amyloid plaques in a time- and dose-dependent manner. Furthermore, aducanumab was associated with a slowing in the rate of clinical decline.

Following these promising findings, Biogen conducted 2 double-blind, randomized, placebo-controlled, parallel-group phase 3 trials – EMERGE (NCT02484547) and ENGAGE (NCT02477800) – beginning in August 2015.^5,10 ENGAGE enrolled patients at 187 sites in North America, Europe, Asia, and Australia,  and EMERGE recruited patients at 194 sites in North America, Europe, and Asia.⁵ The 2 trials were practically identical in their design, and evaluated the safety and efficacy of different aducanumab doses in patients with early AD.¹¹ Collectively, the trials enrolled 3285 patients with confirmed amyloid pathology and mild cognitive impairment and mild dementia due to AD, and planned to provide 18-month outcome data. The primary end point was the effect of aducanumab on CDR-SB at 18 months. Secondary outcomes included changes in the MMSE, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory-Mild Cognitive Impairment (ADCS-ADL-MCI) scales. Patients were randomized on a 1:1:1 basis to receive low-dose aducanumab (3 or 6 mg/kg), high-dose aducanumab (10 mg/kg), or placebo.

The EMERGE and ENGAGE trials were terminated in March 2019 after an interim analysis predicted that they were unlikely to meet their primary outcomes.¹⁰ However, in October 2019, Biogen announced that a subsequent analysis based on additional follow-up data in a larger dataset showed that the EMERGE trial had met its primary outcome. In EMERGE, high-dose aducanumab reduced clinical decline as measured by the primary and secondary endpoints. ENGAGE did not meet its primary outcome, but in a post hoc analysis, a subgroup of patients exposed to high-dose aducanumab declined more slowly, supporting the findings of EMERGE. Table 2 and Table 3 present results of the phase 3 trials.¹¹ Furthermore, the benefits of aducanumab were supported by the findings of the long-term extension of the PRIME trial.⁵ A total of 143 patients opted to continue in the long-term extension study, with patients producing data for up to 3 years. All patients received aducanumab throughout the extension and continued to experience a time- and dose-dependent reduction in amyloid plaques.

Findings from the ENGAGE, EMERGE, and PRIME trials formed the basis of Biogen’s application requesting approval of aducanumab.⁵ The FDA determined that, although the phase 3 data were not fully conclusive regarding the benefits of aducanumab on cognitive function, the medication reduces beta-amyloid plaque levels. These data were the foundation for the accelerated approval, which allows for early approval of drugs for serious conditions for which there are no effective treatments.¹² Accelerated approval is based on the effect observed on a surrogate endpoint – in this case, the reduction in beta-amyloid – rather than clinical outcomes. The press release from the FDA stated that effect of aducanumab on the surrogate endpoint “is reasonably likely to predict a clinical benefit to patients.”²

Controversy
The approval of the first potentially disease-modifying medication for AD has generated enthusiasm and optimism among patients, families, and advocacy groups, including the Alzheimer’s Association.¹³ Formal approval has also revived the interest of investors and pharmaceutical companies in the development of agents for neurodegenerative conditions.¹² Nonetheless, neurology experts, statisticians, and others are skeptical regarding the purported benefits of aducanumab.¹³ In fact, its approval has sparked outrage for numerous reasons, and several organizations and members of the scientific community have challenged the FDA regarding the decision. One such organization was the American Geriatrics Society (AGS), which issued a letter to the FDA outlining concerns.¹⁴ As the letter pointed out, the phase 3 clinical trials for aducanumab were incomplete (halted mid-way for futility after an interim analysis) and unpublished. Moreover, only 1 trial (EMERGE) demonstrated a benefit in a post hoc analysis of data limited to the higher dose, while results from the other phase 3 trial (ENGAGE) were negative. The AGS noted that the decision to rely on 1, incomplete trial as the basis for approval seems to oppose regulatory guidance, which recommends additional characteristics to “support the persuasiveness of a single trial.” Furthermore, 2 positive studies are more convincing than 1 study for a disease such as AD with high interpersonal heterogeneity among patients.¹⁵

The controversy is amplified by the argument that the clinical relevance of the positive findings for aducanumab is ambiguous.¹⁶ The benefit seen in the EMERGE trial only equated to about 3 months’ worth of delay in CDR-SB decline over a year, and it is undetermined whether this benefit is clinically meaningful. Furthermore, the negative results of the ENGAGE trial question the credibility and reproducibility of the claimed benefits. At the FDA Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee in November 2020, Biogen proposed several post hoc explanations for the negative results from the trial.^16,17 However, a statistician for the FDA noted that performing a post hoc analysis of the positive trial alone introduced substantial bias.^16,18 In particular, the differences in trial execution and variations in patient characteristics raised questions about dose effects and subgroup analyses. Furthermore, there were no statistically significant clinical benefits for the high dose when both phase 3 trial data were combined.¹⁶ Another area of dispute at the meeting concerned the reliance of the FDA on a surrogate marker that has not been validated, in order to justify accelerated approval.¹⁹ According to neurology experts and the statistician for the FDA, the relationship between the reduction in amyloid plaques and cognitive improvement is unclear. Several trials for other medications that also reduced amyloid levels did not show cognitive benefit, and some trials actually demonstrated cognitive worsening. Therefore, due to the negative statistical review and uncertainties regarding clinical significance, 10 out of 11 expert panelists voted against aducanumab at the FDA meeting; 1 panelist abstained.¹³

Not only do arguments exist that the benefits of aducanumab are meager, but there are also significant safety concerns with the medication.¹⁹ Amyloid-related imaging abnormalities were experienced by 34% of patients in the high-dose group in the EMERGE trial, and 35.5% of patients in the ENGAGE trial. The adverse effects related to ARIA can be asymptomatic, but severe in some cases. Therefore, MRI scans are integrated into the safety monitoring routine for aducanumab-treated patients.

Cost also becomes a concern with routine scans and monthly aducanumab infusions.^13,19 Amyloid positron emission tomography scans cost between $5,000 to $7,000 per study and are not reimbursed by insurance companies.¹⁹ Moreover, Biogen announced that the annual cost of aducanumab is approximately $56,000 per patient; many patients may potentially continue on the drug for years.¹³ Of note, this price starkly contrasts with an annual cost estimate of $3,000 to $8,400 noted within a cost-effectiveness analysis from the Institute for Clinical and Economic Review.²⁰ It is also unclear how third-party payors will reimburse for the medication.¹³ As Medicare coverage remains uncertain, Biogen has started to offer free initial doses of aducanumab to some patients, although the company has not shared the specifics regarding this initiative.²¹ Just as noteworthy as the enormous financial costs to the healthcare system is the burden on neurologists to appropriately select, counsel, and monitor patients on aducanumab.¹⁶ Neurologists will have to dedicate time to counsel patients and caregivers on expectations for treatment, as well as provide them with unbiased information regarding benefits and risks. This is particularly challenging since there has been no peer-reviewed publication on aducanumab to date.

Another major area of contention regards the approval process for aducanumab, which has been met with intense scrutiny at nearly every level.¹³ Table 4 provides a timeline of events associated with the approval.^10,16,22 Of note, the FDA required Biogen to conduct a post-approval trial to confirm the clinical benefit of aducanumab, as part of the accelerated approval process.¹³ Biogen anticipates that this trial will begin in 2022. As stated earlier, the decision by the FDA to approve aducanumab came after an advisory committee (comprising neurology experts) voted nearly unanimously against approval. Following the approval, 3 members of the FDA advisory committee resigned due to concerns regarding the decision-making process. Accusations regarding the close collaboration between the FDA and Biogen, lowering of standards for drug approval, and lack of transparency all resulted in the integrity of the agency being questioned.²³ Following these allegations, the acting FDA commissioner conducted an internal inquiry, and later called for a federal investigation of the approval proceedings of the agency.^23,24 In response, the Office of the Inspector General of the Department of Health and Human Services confirmed that it will review the accelerated approval process and investigate how the agency interacts with outside parties.²⁵ Lastly, the approval of aducanumab may have several unintended consequences.²⁶ These include complicating future trials in AD, setting back interest in other targets, and undermining regulatory standards.^26,27 For example, manufacturers of other drugs that reduce amyloid levels as a surrogate marker could swamp the FDA with requests for approval, or future studies may be required to compare an investigational drug to aducanumab instead of placebo.¹³ Above all, the experience with aducanumab may foster a culture of mistrust among patients, federal agencies, and healthcare providers.²⁷

Conclusion
In summary, the ultimate answer to the question on whether the approval of aducanumab reflects 1 step forward, or 2 steps backward, as it pertains to the treatment of AD remains in flux. On one hand, the approval hopefully gives new impetus to research aimed at developing clinically effective treatments for this serious disease. On the other hand, the approval will certainly reverberate for years as several questions and uncertainties linger and information regarding this topic continues to evolve.

References

1. FDA grants accelerated approval for ADUHELM™ as the first and only Alzheimer’s disease treatment to address a defining pathology of the disease. Biogen. June 7, 2021. Accessed July 17, 2021. https://investors.biogen.com/news-releases/news-release-details/fda-grants-accelerated-approval-aduhelmtm-first-and-only?cid=aff-aduhelm-hp_cta_biogen-app_news_release
2. FDA grants accelerated approval for Alzheimer’s drug. U.S. Food and Drug Administration. June 7, 2021. Accessed July 17, 2021. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
3. FDA approves updated ADUHELM™ prescribing information to emphasize population studied in clinical trials. Biogen. July 8, 2021. Accessed July 17, 2021. https://investors.biogen.com/news-releases/news-release-details/fda-approves-updated-aduhelmtm-prescribing-information-emphasize
4. Aduhelm. Package insert. Biogen; 2021.
5. Aduhelm (aducanumab). Alzheimer’s News Today. June 7, 2021. Accessed July 17, 2021. https://alzheimersnewstoday.com/aducanumab/?cn-reloaded=1
6. Absolute bioavailability of a single, fixed subcutaneous dose of aducanumab in healthy participants. ClinicalTrials.gov identifier: NCT02782975. Updated January 13, 2017. Accessed June 7, 2021. https://clinicaltrials.gov/ct2/show/NCT02782975
7. Single and multiple ascending dose study of aducanumab (BIIB037) in Japanese participants with Alzheimer’s disease (PROPEL). ClinicalTrials.gov identifier: NCT02434718. Updated August 21, 2020. Accessed June 7, 2021. https://clinicaltrials.gov/ct2/show/NCT02434718
8. Single ascending dose study of BIIB037 in participants with Alzheimer’s disease. ClinicalTrials.gov identifier: NCT01397539. Updated March 23, 2015. Accessed June 7, 2021. https://clinicaltrials.gov/ct2/show/NCT01397539
9. Multiple Dose Study of Aducanumab (BIIB037) (Recombinant, Fully Human Anti-Aβ IgG1 mAb) in Participants With Prodromal or Mild Alzheimer’s Disease (PRIME). ClinicalTrials.gov identifier: NCT01677572. Updated August 3, 2020. Accessed June 7, 2021. https://clinicaltrials.gov/ct2/show/NCT01677572
10. Aduhelm. Alzforum. June 7, 2021. Accessed July 17, 2021. https://www.alzforum.org/therapeutics/aduhelm
11. Haeberlein SB, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Biogen. 2019. Accessed July 17, 2021. https://investors.biogen.com/static-files/ddd45672-9c7e-4c99-8a06-3b557697c06f
12. Tagliavini F, Tiraboschi P, Federico A. Alzheimer’s disease: the controversial approval of aducanumab. Neurol Sci. 2021;42(8):3069-3070. doi:10.1007/s10072-021-05497-4
13. Park A. The controversy over the FDA’s approval of the first Alzheimer’s treatment keeps growing. TIME. June 11, 2021. Accessed July 17, 2021. https://time.com/6072980/alzheimers-drug-approval-controversy/
14. Hollmann P, Lundebjerg NE. Food and Drug Administration’s review of Biogen’s drug aducanumab for Alzheimer’s disease. Letter. The American Geriatrics Society. June 2, 2021. Accessed July 17, 2021. https://www.americangeriatrics.org/sites/default/files/inline-files/American%20Geriatrics%20Society_Letter%20to%20FDA%20Biogen%20Drug%20for%20Alzheimer%27s%20%28June%202021%29%20FINAL%20%281%29.pdf
15. Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement. 2021;17(4):696-701. doi:10.1002/alz.12213
16. Knopman DS, Perlmutter JS. Prescribing aducanumab in the face of meager efficacy and real risks [published online ahead of print, 2021 Jul 7]. Neurology. 2021;10.1212/WNL.0000000000012452. doi:10.1212/WNL.0000000000012452
17. November 6, 2020: meeting of the peripheral and central nervous system drugs advisory committee meeting announcement. U.S. Food and Drug Administration. Updated February 5, 2021. Accessed August 30, 2021. https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting#event-information
18. Kuller LH, Lopez OL. ENGAGE and EMERGE: truth and consequences? Alzheimers Dement. 2021;17(4):692-695. doi:10.1002/alz.12286
19. Hershey LA, Tarawneh R. Clinical efficacy, drug safety and surrogate endpoints: has aducanumab met all of its expectations? [published online ahead of print, 2021 Jul 7]. Neurology. 2021;10.1212/WNL.0000000000012453. doi:10.1212/WNL.0000000000012453
20. Lin G, Whittington MD, Synnott PG, et al. Aducanumab for Alzheimer’s disease: effectiveness and value. Institute for Clinical and Economic Review. Published June 30, 2021. Accessed July 17, 2021. https://icer.org/wp-content/uploads/2020/10/ICER_ALZ_Revised_Evidence_Report_06302021.pdf
21. Beasley D. Biogen offers free Alzheimer’s drug as Medicare payment uncertainty remains. Reuters. August 30, 2021. Accessed September 3, 2021. https://www.reuters.com/world/us/biogen-provides-free-aduhelm-us-clinics-await-medicare-payment-2021-08-30/
22. Stewart J. Aduhelm FDA approval history. Drugs.com. July 15, 2021. Accessed July 17, 2021. https://www.drugs.com/history/aduhelm.html
23. Belluck P, Kaplan S, Robbins R. How an unproven Alzheimer’s drug got approved. The New York Times. July 19, 2021. Accessed August 17, 2021. https://www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html
24. Brauser D. FDA head calls for investigation into agency’s approval of aducanumab (Aduhelm). Medscape. July 9, 2021. Accessed July 17, 2021. https://www.medscape.com/viewarticle/954544
25. Young KD. FDA’s accelerated drug approval process under investigation by OIG. August 5, 2021. Accessed August 17, 2021. https://www.medscape.com/viewarticle/956039
26. Mullard A. Landmark Alzheimer’s drug approval confounds research community. Nature. 2021;594(7863):309-310. doi:10.1038/d41586-021-01546-2
27. Walsh S, Merrick R, Milne R, Brayne C. Aducanumab for Alzheimer’s disease? BMJ. 2021;374:n1682. doi:10.1136/bmj.n1682

Prepared by:
Honey Joseph, PharmD
PGY2 Drug Information Resident
University of Illinois at Chicago College of Pharmacy

October 2021

The information presented is current as of September 10, 2021. This information is
intended as an educational piece and should not be used as the sole source for clinical decision-
making.