By: Aamir S. Dave, PharmD Candidate c/o 2023 Judith L. Beizer, PharmD, BCGP, FASCP, AGSF

Alzheimer’s and Dementia

             Dementia is characterized by the loss of memory and other cognitive abilities that interfere with daily life. Alzheimer’s is a progressive neurological disease and is the most common type of dementia, accounting for greater than 60-80% of dementia cases.¹ Although Alzheimer’s is not a normal part of aging, increasing age is the greatest known risk factor of this disease.¹ As recently as June 7th, 2021 a new treatment for Alzheimer’s in the form of aducanumab (Aduhelm^TM) has been approved, and has been met with intense controversy.²

The pathology of Alzheimer’s involves two key markers: neurofibrillary tangles of tau protein and beta-amyloid neurotic plaques.³ Neurofibrillary tangles of tau protein are intracellular deposits that can be used to aid in the diagnosis of Alzheimer’s by looking at elevated tau protein levels in the cerebrospinal fluid (CSF). Beta-amyloid is a 36-43 amino acid long peptide. Beta-amyloid levels in the CSF can also be used as a diagnostic tool for Alzheimer’s. The formation of beta-amyloid plaques starts from the Amyloid Precursor Protein (APP).² APP can be processed by two different enzymes: alpha-secretase and beta-secretase. When APP is cut by alpha-secretase and then by gamma-secretase, a non-amyloid compound is formed that is harmless. However, when APP is cut by beta-secretase first and followed by gamma-secretase, it creates the toxic beta-amyloid neurotic plaques seen in Alzheimer’s. Beta-amyloid is chemically “sticky” and clumps into entanglements called “fibrils.” These fibrils form a mat called beta-sheets which are responsible for blocking cell-to-cell communication and activate an inflammatory immune system process that results in the destruction of brain cells.² Understanding this process has made beta-amyloid a target for potential treatment options of Alzheimer’s disease. This treatment target led to the development of aducanumab.

Cholinesterase Inhibitors, NMDA Antagonists, and the Treatment of Alzheimer’s

The treatment of Alzheimer’s involves the use of cholinesterase Inhibitors. This includes drugs like donepezil, rivastigmine, and galantamine. The rationale behind use of these drugs involves the neurotransmitter acetylcholine and its levels within key neuronal synapses that affect memory and cognition. Brain acetylcholine levels in patients with Alzheimer’s and other types of dementia were significantly lower than patients of normal cognitive ability, relative to age group.⁴ Additionally, it was found that the use of anticholinergic drugs in patients with Alzheimer’s had the potential to make them forget things from the night before. These findings led many researchers to associate the loss of cholinergic transmission with dementia. Cholinesterase’s are a class of enzymes involved in the breakdown of acetylcholine to acetic acid and choline.⁴ By inhibiting this enzyme, acetylcholine levels increase, thereby correcting the cholinergic shortage. This class of drugs does not cure Alzheimer’s but instead slows the progression of cognitive decline.

Memantine is another common drug used for Alzheimer’s. It is an N-methyl-D-aspartate (NMDA) antagonist. It is believed that over-stimulation of the NMDA receptor by the neurotransmitter glutamate also contributes to the neurocognitive decline seen in Alzheimer’s.⁵ Memantine has been shown to improve daily living scores in multiple functionality tests. In a meta-analysis conducted on memantine monotherapy use in Alzheimer’s patients, memantine modestly improved cognitive function, Alzheimer’s-associated behavioral function, activities of daily living, global function assessment, and stage of dementia when compared with placebo.⁵ Similar to the cholinesterase inhibitors, memantine does not cure Alzheimer’s but has been shown to slow progression.⁵

The failure of both these drug classes as monotherapy to stop the progression of Alzheimer’s gave rise to the idea that Alzheimer’s is a multifactorial disease and many different biological markers may have to be addressed to slow the progression.⁴ This led to the use of cholinesterase Inhibitors and memantine in combination. While there was some clinical benefit to the use of these drugs in combination, the overall effect was not clinically significant or sustainable long term.⁴

Aducanumab’s (AduhelmTM) Development and Purpose

             Aducanumab-avwa (Aduhelmᵀᴹ) is a recombinant human IgG1 monoclonal antibody (mAB) that is expressed in a Chinese hamster ovary cell line. It targets a conformational epitope on the beta-amyloid protein in both its soluble oligomeric forms and insoluble plaque forms with high affinity.⁶ Aducanumab was originally derived by Neuroimmune, a biotech company in Switzerland. It was taken from healthy donors who were cognitively normal. The researchers hypothesized that these donors had immune systems that could successfully resist Alzheimer’s disease. They used a process called “reverse translational medicine” to turn the derived antibodies into therapeutical antibodies.¹¹

Dosing of Aduhelmᵀᴹ

The Food and Drug Administration (FDA)-authorized dose of aducanumab is 10mg/kg actual body weight given as an IV infusion, which must be achieved through an initial titration sequence (see table 1) that occurs over the first 7 infusions or 28 weeks.⁶ Each infusion is given over approximately one hour preferably every 4 weeks, but at least 21 days apart. For missed dosing, resume administration of the same missed dose as soon as possible. There is no adequate data to determine if Aduhelmᵀᴹ can be used safely in pregnancy or lactation. However, in animal studies of female rats at concentrations 0, 100, 300, or 1000 mg/kg/week; there was no adverse effect on embryofetal development.⁶ There were also no adverse effects on prenatal and postnatal development throughout pregnancy and lactation.

The monitoring parameters for Aduhelmᵀᴹ include a brain MRI within one year prior to the start of treatment, before the 7th infusion (the first full 10mg/kg dose), and the 12th infusion.⁶

Aduhelm^TM is available in 2 different volumes, 1.7 mL and 3.0 mL. Both have a concentration of 100mg/ml and come as single-dose vials.  Aduhelm^TM can be added to an infusion bag of 100 mL of 0.9% sodium chloride injection, USP.⁶ It is not recommended to use other diluents to dilute Aduhelm^TM. After dilution it should be used immediately, however, it can be refrigerated at 2-8 degrees C for 3 days or stored at room temperature up to 30 degrees C for 12 hours.⁶

Aduhelm^TM Clinical Trials

There were 2 major trials involved in the accelerated FDA-approval of Aduhelm^TM for the treatment of Alzheimer’s. These trials were the ENGAGE (NCT 02477800) and EMERGE (NCT 02484547) phase 3 clinical trials. Both trials were randomized, multicentered, double-blind, placebo-controlled, parallel group studies in patients with early-stage Alzheimer’s. The primary outcome was a 78-week change from baseline in Clinical Dementia Rating scale Sum of Boxes (CDR-SB score.) The CDR-SB score assesses three domains of cognition: memory, orientation, and problem-solving. The score for each category is defined by a degree of severity ranging from 0-3, with a score of “0” being no performance disability and a score of “3” being severe performance disability. The scores are summed for a total score range between 0-18. There were 3 treatment arms in both studies (placebo, low-dose Aduhelm^TM, and high-dose Aduhelm^TM.) Dosing, in both trials, was based on APOE (Apolipoprotein) ε4 carrier status. APOE ε4 is a protein associated with the earlier onset and increased risk of dementia.⁷ In the low-dose group, APOE ε4 carriers received 3 mg/kg and non-carriers received 6 mg/kg. APOE ε4 carriers in the high-dose group also received 6 mg/kg, while non-carriers received 10 mg/kg. 

The EMERGE trial found a statistically significant difference in the primary outcome in the high dose arm only (difference vs. placebo -0.39 [95% CI -0.69 to -0.09].)⁷ While this outcome is statistically significant, clinical significance was not reached as a minimal change of the CDR-SB score of 1-2 points is required for that distinction. The ENGAGE trial observed no statistically significant difference in the change from baseline in CDR-SB in both the low and high dose arms.⁷ In a meta-analysis of both studies, the combined data showed no statistically significant results in the high dose or low dose treatment arms (difference in CDR-SB vs. placebo -0.18 [95% CI -0.50 to 0.24] and (-0.21 [95% CI -0.43 to 0.00]) respectively.⁷ The meta-analysis had high heterogeneity between the EMERGE and ENGAGE with an I²= 74.65% and a low heterogeneity between the EMERGE and ENGAGE with an I²= 0%.

The outcomes of the EMERGE and ENGAGE trials failed to provide definitive and justifiable proof of the efficacy of Aduhelm^TM for Alzheimer’s.  However, in post-hoc analyses, the FDA and the manufacturer, Biogen, attempted to explore a hypothesis for the differing results of the EMERGE and ENGAGE trials. This led to the finding that 9 of the high-dose arm participants were identified as “rapid progressors” as their CDR-SB score worsened by 8 points over the 78-week period. Whereas the other arms in both trials only had 4-5 “rapid progressors.” When removing these outliers, the ENGAGE trial did show benefit in Aduhelm^TM. However, statistical significance could not be determined, and the result was still not clinically significant.⁷ This is why FDA approval of aducanumab has been controversial and has been met with intense scrutiny. 

In a safety analysis, ARIA (Amyloid-Related Imaging Abnormalities) due to edema and effusion (ARIA-E) or hemorrhage (ARIA-H) was the safety event of highest concern. The incidence of ARIA-E or ARIA-H at approved dosing (10mg/kg) was 41.3%.⁷ In both studies, dosing was stopped until ARIA was resolved. Other common adverse events were headache (20.5% at 10mg/kg), falls (15.0% at 10mg/kg) and diarrhea (8.9% at 10mg/kg).⁷

On November 9^th, 2021 it was reported that the first suspected death due to cerebral edema, believed to be ARIA-E induced by aducanumab, occurred in a 75 year old female patient who had been taking the drug for their Alzheimer’s disease. Not much has been released about the patient but it is believed that the patient had no other conditions that could have caused the cerebral edema. In a statement to Reuter’s (a news agency company), Biogen said “We continue to work with the reporting physician as well as global regulators to further understand the case.”⁹

Discussion

The efficacy of Aducanumab for the treatment of Alzheimer’s is questionable despite its accelerated FDA approval. Its inability to show clinically significant efficacy at the approved dosing raises concern about the effectiveness it will have outside the strict parameters of a clinical trial. It is important to note that both the ENGAGE and EMERGE clinical trials were stopped prior to completion as the researchers believed they were unlikely to reach their primary endpoint on prespecified criteria. It was not until the FDA decided to work with Biogen that statistical significance was found in only one treatment arm out of one of the two trials.¹⁰ 

Aducanumab’s safety profile shows a high risk of ARIA, headache, and falls which is highly significant since most patients that will be using Aduhelm^TM will be of advanced age and are more likely to be effected by these adverse effects. As of November 11^th, there is one case of a cerebral edema causing death in a patient on Aduhelm^TM. This is still being investigated but early results suggest this cerebral edema was ARIA-E induced and was caused by Aduhelm^TM.⁹ The cost of Aduhelm^TM is estimated to be around $56,000 per year or $4,312 per infusion for an “average weight patient.”⁸ This is an extremely expensive price to pay for a drug that has non-convincing evidence proving its efficacy. Aduhelm^TM is also unlikely to be covered by Medicare and most private insurances.⁹

Upon initial approval, the Aduhelm^TM package insert stated that it was indicated for all patients with Alzheimer’s Disease.¹⁰ However, this indication does not accurately reflect the population Aduhelm^TM was tested in. A week after the approval of Aduhelm^TM the FDA had to revise the package insert to state:  “indicated for patients with mild Alzheimer’s Disease” to match the population it was tested in.¹⁰ The seemingly overwhelming amount of backlash of Aduhelm^TM seems justified when every step leading up to Aduhelm^TM approval is shrouded in controversy. 

The controversial efficacy of Aduhelm^TM calls into question the use of amyloid targeting agents for the treatment of Alzheimer’s. As of August 2021, there is no evidence to suggest that Aduhelm^TM will change the current treatment guidelines for Alzheimer’s away from the cholinesterase inhibitors and memantine. A similar drug to Aduhelm^TM named Donanemab is currently undergoing Phase 3 clinical trials. Both drugs are beta-amyloid plaque targeting monoclonal antibodies. It will be interesting to see how these drugs compare.

References

1. Alzheimer’s Association. What is alzheimer’s disease. Alzheimer’s and Dementia. https://www.alz.org/alzheimers-dementia/what-is-alzheimers. Published June 1, 2021.
2. Alzheimer’s Association. Beta-amyloid and the amyloid hypothesis. Alzheimer’s and Dementia. https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf. Published March 1, 2017.
3. Hane FT, Robinson M, Lee BY, et al. Recent progress in alzheimer’s disease research. J Alzheimers Dis. 2017; 57 (3):645-665. 
4. Sharma K. Cholinesterase inhibitors as alzheimer’s therapeutics. Mol Med Rep. 2019; 20 (2):1479-1487. 
5. Matsunaga S, Kishi T, Iwata N. Memantine monotherapy for alzheimer’s disease: a systematic review and meta-analysis. PLoS One. 2015; 10 (4): e0123289.
6. Aducanumab-avwa (Aduhelm) [package insert]. Cambridge, MS ; Biogen, Inc.; Revised July 1, 2021. 
7. Lin GA, Whittington MD, Synnott PG, et al. Aducanumab for alzheimer’s disease effectiveness and value. Institute for Clinical and Economic Review. 2021; 1 (1):1- 111
8. Higgins-Dunn N. Biogen’s $56K price on Aduhelm ‘simply unacceptable,’ Alzheimer’s Association says after vouching for FDA approval. FiercePharma. https://www.fiercepharma.com/pharma/biogen-s-56k-price-tag-for-aduhelm-simply-unacceptable-and-needs-fixed-alzheimer-s. Published 06/14/2021. Last Updated June 14, 2021.
9. Terry M. Biogen Investigates Death of 75-Year-Old on Aduhelm. Biospace https://www.biospace.com/article/biogen-investigates-death-in-75-year-old-alzheimer-s-patient-on-aduhelm/
10. Levy HB. Accelerated approval of Aducanumab: where do we stand now. Annals of Pharmacotherapy. 2021; 1 (1)
11. Lemere CA, Crehan H. Anti-Amyloid-β immunotherapy for alzheimer’s disease. Developing Therapeutics for Alzheimer’s Disease. 2016; 1 (1): 193-226 https://www.sciencedirect.com/topics/immunology-and-microbiology/aducanumab

Published by Rho Chi Post