By Minitha Jacob, PharmD Candidate, and Hannah Grice, PharmD
Alzheimer’s disease (AD) is considered the most common cause of dementia and accounts for about 60% of cases (approximately 5.7 million adults) in the US.
Alzheimer’s is primarily seen in patients aged 65 years and older.
Statistics predict the number of cases to double by 2050.1
Patients with Alzheimer’s can live for 4-8 years on average after diagnosis, while few can survive as long as 20 years.
The exact etiology of AD is still unknown, but studies have discovered several proposed hypotheses that lead to its development.
Some pathologies in the brain include aggregation of beta-amyloid protein leading to the formation of plaques, hyperphosphorylation of the tau protein leading to neurofibrillary tangles, synaptic failure, depletion of neurotransmitters, mitochondrial dysfunction, and oxidative stress by free radicals.2
These mechanisms can disrupt the vital communication between nerve cells in the brain and trigger immune cells to initiate inflammation while disabling nerve cells.
More than half of early-onset AD is due to chromosomal alterations that affect amyloid precursor protein processing.
One of three secretase enzymes (alpha) that break down proteins is non-pathological, while the activity of the other two (beta and gamma) prove to be pathological.
The accumulation of the beta-amyloid is predicted to lead to progressive neurological deterioration.
However, whether this is the primary pathology in all AD forms is unknown, and researchers continue to search for a definitive understanding of the disease.1
Several treatment options have been studied and approved to treat the cognitive symptoms of Alzheimer’s.
These include cholinesterase inhibitors and glutamate regulators along with orexin receptor antagonists to address insomnia in dementia patients.3
Recent focus is on amyloid-beta, and the use of monoclonal antibodies to remove the pathological protein that forms the plaques contributing to cell death and tissue loss in AD.4
Aduhelm® (generic name aducanumab), developed by Biogen Inc., is the first anti-amyloid antibody that is FDA approved to treat early Alzheimer’s.
This novel therapy was recently approved for patient use in June 2021 and is the first approved AD drug in 20 years.
The intravenous (IV) infusion therapy works directly against soluble and insoluble forms of amyloid-beta to prevent and/or slow down plaque formation in the brain.5
With the treatment of these plaques in the brain, this drug has been studied to determine if it may delay clinical decline and improve cognition and/or function in AD patients.
Aduhelm’s approval has been controversial, and the drug has met with disapproval and apprehension by clinicians and even members of FDA advisory committees.
In March of 2019, Biogen terminated two Phase III clinical trials and one Phase I trial of aducanumab after preliminary data showed they failed their futility analysis.6
The analysis acknowledged there was insufficient evidence that the drug halted amyloid accumulation and, consequently, would not benefit patients.
Later, Biogen said that the initial data was only collected through December 2018.
Additional evaluated data showed a different outcome when patients received Aduhelm® in high doses.
A small Phase I trial was also conducted to evaluate the drug’s effectiveness in high doses to halt amyloid accumulation.
The company reported that with higher doses, patients “experienced significant benefits on measures of cognition and function such as memory, orientation, and language,” as well as benefits in daily activities.7
There is evidence of serious side effects when taking Aduhelm, such as brain swelling, intracranial bleeding, falls, and worsening confusion/delirium.
Despite the side effects found with the drug, Biogen deemed that the benefits outweighed the risks, and decided to submit their drug to the FDA under the “accelerated approval” program.
The program gives earlier drug authorization for novel treatments of serious diseases that have unmet needs.
The program allows companies to treat an unmet medical need based on a surrogate endpoint, such as a lab value, radiographic image, and/or a physical sign, to predict clinical benefit.8
Biogen claims that their drug shows a reduction in amyloid formation and plaques in the brain.
However, clinicians and patients question whether this will translate to slowing or reversing memory and thinking symptoms in Alzheimer’s patients.
EMERGE Study Analysis
The EMERGE study was a Phase III randomized, two double-blind, parallel-group study to evaluate the efficacy of monthly aducanumab doses in early AD patients to observe slowing cognitive and functional impairment vs. placebo.9,10
A sample of 1,638 patients between the ages of 50 to 85 was included that met all clinical criteria for mild cognitive impairment due to normal or mild AD.
Researchers selected patients who showed evidence of cognitive impairment at screening, a Clinical Dementia Rating (CDR) of 0.5, and a positive amyloid Positron Emission Tomography (PET) scan confirming amyloid pathology.
Study subjects were randomized 1:1:1 to receive a low dose (3 mg/kg for ApoE e4 carriers or 6 mg/kg for noncarriers), a high dose of 10 mg/kg, or a placebo every 4 weeks for 18 months and titrated for up to 6 months to the maximum target dose.
Treatment was followed by an optional, dose-blind, long-term extension period.
The primary outcome was the observed change from baseline CDR-Sum of Boxes at week 78, while the secondary outcomes consisted of any change from baseline in Mini-Mental State Examination (MMSE) score, AD Assessment Sale-Cognitive Subscale (ADAS-Cog) scale, and/or AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL-MCI) score.
The study results showed that Aduhelm high dose demonstrated a statistically significant difference from baseline in CDR-SB vs placebo (-0.39, -22%, P = 0.0120).
Secondary endpoints for Aduhelm high dose also showed statistically significant difference from baseline in MMSE (0.6, -18%, P = 0.0493), ADAS-Cog (-1.4, -27%, P = 0.0097), and ADCS-ADL-MCI (1.7, -40%, P = 0.0006).
No statistically significant change was observed between low dose and placebo-treated patients.
The improvements in both CDR-SB and MMSE for high-dose patients, while statistically significant, are small enough that it is difficult to really assume that any clinically significant change occurred in these patients.
ENGAGE Study Analysis
The ENGAGE study was another Phase III randomized, two double-blinded, parallel-group trial that similarly assessed monthly doses of aducanumab and its efficacy in slowing cognitive and functional impairment vs. placebo.9,10
Investigators evaluated 1,647 patients aged 50 to 85 years who met all clinical criteria as mentioned in the EMERGE clinical trial.
Patients were randomized 1:1:1 to receive Aduhelm low dose, Aduhelm high dose, or placebo in the same dosages and time frame of 4 weeks for 18 months as the EMERGE study.
ApoE e4 carriers were also initially titrated to up to the maximum target dose.
The primary outcome for this trial was any observed change from baseline CDR-SB on week 78.
Secondary outcomes evaluated changes from baseline in MMSE, ADAS-Cog, and ADCS-ADL-MCI scales as well.
Despite similar trial arms and treatments, the ENGAGE results did not show a statistically significant difference between the Aduhelm-treated patients’ low dose (-0.18, -12%, P = 0.225) or high dose (0.03, 2%, P = 0.833) and the placebo-treated patients in CDR-SB score at 78 weeks.
PRIME Study Analysis
The PRIME study, a Phase I randomized, double-blind, placebo-controlled, dose-ranging trial, evaluated patients who received a fixed dose of Aduhelm for 12 months.9
The trial studied 197 subjects, between the ages of 51 to 91 years, based on clinical criteria confirming prodromal AD or mild AD.
Patients received a monthly multiple-dose regimen of Aduhelm 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg against a placebo group, with dosages being titrated to 10 mg/kg over 44 weeks for a total of 12 months.
The trial’s primary outcome was the safety and tolerability of Aduhelm by measuring adverse events, laboratory assessments, vital signs, neurological and physical exams, ECG data, and brain MRI scans.
The trial’s secondary outcome was to assess the multiple-dose serum concentrations of the drug and to evaluate immunogenicity after multiple-dose administration.
Researchers observed the change from baseline in florbetapir (a radiopharmaceutical compound) PET imaging in the brain, multiple-dose pharmacokinetic (PK) profile of aducanumab, and change from baseline in anti-aducanumab antibodies.
The clinical assessments made from this study were mainly exploratory and were consistent with findings from the EMERGE trial—there was a statistically significant change from baseline with high dose Aduhelm vs. placebo.
Although, the trial found that patients receiving high doses of the drug did have more signs of brain swelling and hemorrhaging identified as amyloid-related imaging abnormalities-edema or ARIA-E.
Headaches were also commonly found in some patients receiving the high dose.
Why did the FDA approval of the drug despite all three trials being halted and only having one of those studies meet its original primary endpoint?
Biogen decided to conduct a posthoc analysis on their existing data, which allows the performance of multiple tests.11
Some committee members of the Peripheral and Central Nervous System Drugs Advisory Committee were concerned about the posthoc results and felt the results were too weak to use as a basis for drug approval.
The FDA strongly argued that there was “substantial evidence that the drug reduces amyloid plaque, and that this reduction is reasonably likely to predict clinical benefit,” which does fall under the criteria for the accelerated approval program.
However, it is also a tacit admission that no clinical benefit has been observed in the use of this drug.12
Along with this, adverse events with Aduhelm do pose some concern for patients and clinicians.
Biogen recently presented a poster at the 2021 Alzheimer’s Association International Conference (AAIC) in which they addressed the characteristics of amyloid-related imaging abnormalities (ARIA) that occurred with high-dose aducanumab.
They concluded that about 76% of treated patients with ARIA showed to be asymptomatic, ARIA generally showed as being mild or moderate in radiographic severity, and that ARIA severity alone is not predictive of symptomatic status.11
The FDA has stated that they appropriately considered different perspectives and reviewed all relevant data.
In search of further corroboration, the FDA is requiring Biogen to conduct post-approval studies or Phase 4 confirmatory trials to verify anticipated clinical benefit.12
If the trials do not verify clinical benefit, FDA is authorized to remove the drug from the market.
Alzheimer’s disease is a devastating condition that causes patients to lose their memory and reduces cognitive function.
This progression often leads to patients no longer responding to their environment or speaking with their loved ones and eventually may end in complications that result in death.
This much is true: the need for treatment is imperative; however, does the existing data for Aduhelm and the unmet need of this population warrant its use in practice?
PharmD Live concludes that it is too early to use Aduhelm as a first- or second-line therapy despite its potential effect on the accumulation of amyloid plaques.
Patients with AD and their loved ones currently face a disease for which there are no cures and few treatments that provide meaningful benefit.
While approval of a drug such as Aduhelm certainly adds a potential therapy option, it also may represent false hope and potentially dangerous side effects for these vulnerable patients and families.
Health professionals eagerly anticipate further evidence of benefit as more patients receive Aduhelm in post-approval use.
Interested in additional reading about this topic?
About the authors
Hannah Grice, PharmD, graduated from Texas Tech University Health Sciences Center School of Pharmacy in 2021 and has been with PharmD Live since May of 2020. Dr. Grice’s interests include geriatrics, specialty pharmacy, and collaborative disease state management. She lives in Fort Worth, TX, with her husband and basset hound. In her free time, she enjoys playing tennis and hosting game nights with friends and family.
Minitha Jacob has experience as an ER scribe at a Trauma II hospital and as a hospital intern performing medication reconciliations and administering vaccinations. Her goals include applying to residency and specializing in ambulatory care, oncology, or organ transplantation. Minitha is a contributing author for a published textbook on P-glycoprotein signaling cascades. As an independent researcher, she is conducting a research project on correction formulae with QT prolongation. Her hobbies include reading, dancing, baking, streaming shows, and spending time with family and friends.
- Peron EP, Zimmerman KM, Crouse EL, Slattum PW, Hobgood SE. Alzheimer Disease. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. McGraw Hill; Accessed July 24, 2021. https://accesspharmacy-mhmedical-com.ezproxy.ttuhsc.edu/content.aspx?bookid=2577§ionid=226724147
- Alzheimer Disease. In: Wells BG, DiPiro JT, Schwinghammer TL, DiPiro CV. eds. Pharmacotherapy Quick Guide. McGraw Hill; Accessed July 24, 2021. https://accesspharmacy-mhmedical-com.ezproxy.ttuhsc.edu/content.aspx?bookid=2177§ionid=165473459
- FDA-approved treatments for Alzheimer’s. Alzheimer’s Association. https://www.alz.org/media/documents/fda-approved-treatments-alzheimers-ts.pdf. Published June 2021. Accessed July 24, 2021.
- Katzung BG. Special Aspects of Geriatric Pharmacology. In: Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw Hill; Accessed July 25, 2021. https://accesspharmacy-mhmedical-com.ezproxy.ttuhsc.edu/content.aspx?bookid=2988§ionid=250604555
- Aducanumab. In: Lexi-Drugs [database online]. Hudson, Ohio: Wolters Kluwer Health. Updated periodically. Accessed July 22, 2021.
- 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. Alzheimer’s Dement. 2020;17(4):696-701. https://doi.org/10.1002/alz.12213
- Sandrock A. An open letter to the Alzheimer’s disease community from our head of research and Development, Alfred Sandrock, M.D., Ph.D. Biogen. https://investors.biogen.com/news-releases/news-release-details/open-letter-alzheimers-disease-community-our-head-research-and. Published July 22, 2021. Accessed July 22, 2021.
- Accelerated Approval Program. U.S. Food and Drug Administration. https://www.fda.gov/drugs/information-health-care-professionals-drugs/accelerated-approval-program. Published October 26, 2020. Accessed July 23, 2021.
- Biogen Inc. Aduhelm (aducanumab) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s003lbl.pdf. Revised July 2021. Accessed July 24, 2021.
- Haeberlein SB, Hehn CV, Tian Y, et al. EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients with Early Alzheimer’s Disease. Presented at: 2021 Alzheimer’s Association Conference; July 2021; Cambridge, MA.
- Biogen and Eisai Announce ADUHELM™ (aducanumab-avwa) Data Presentations at Alzheimer’s Association International Conference 2021. Biogen. https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-announce-aduhelmtm-aducanumab-avwa-data. Published July 26, 2021. Accessed July 26, 2021.
- Cavazzoni P. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. U.S. Food and Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease. Published June 7, 2021. Accessed July 26, 2021.