A New Horizon in Alzheimer's Treatment

There are approximately 44 million people worldwide living with Alzheimer’s disease or a related form of dementia ⁽¹⁾. The WHO has estimated that the number of individuals with dementia around the world will increase to 78 million and 139 million by 2030 and 2050 respectively⁽²⁾. Due to its population size, South Asia, especially India, will be a major contributor to this increase ⁽³⁾. In India, currently more than 4 million people have some form of dementia ⁽⁴⁾.

The main risk factor for Alzheimer’s disease (AD) is ageing. A study done by The National Institute on Ageing found that the prevalence of AD doubles every five years beyond 65 years ⁽¹⁾. Another study reported that dementia was the seventh leading cause of death across all ages, and fourth amongst individuals greater than 70 years, across the globe ⁽⁵⁾.

Dementia has a disproportionate impact on women. 65% of the deaths in dementia were attributed to women, while disability-adjusted life years (DALYs) were reported to be about 60% higher in women compared to men. Women also provide the majority of informal care for people living with dementia and account for 70% of care-giver hours ⁽²⁾.

Impact on Self

Once a patient is diagnosed with AD, they experience increased stress levels due to a variety of reasons – fears about forgetting their loved ones, becoming a burden to their family, losing their independence and not being able to take care of themselves. Finances are the greatest cause of stress to patients in the early stages of disease, as they are uncertain about having enough money to pay for their care ⁽⁶⁾.

Impact on Caregivers

One to four family members act as caregivers for each individual with Alzheimer’s disease. In 2016, it was reported that 15.9 million family members and friends provided 18.2 billion hours of unpaid assistance to those with Alzheimer’s disease and other forms of dementia in the US, which translates to an economic worth of roughly $230.1 billion. Around 35% of caregivers reported that their health has gotten worse due to care responsibilities ⁽¹⁾.

Current treatment options

Tacrine was the first drug to be clinically used for the treatment of AD ⁽⁷⁾. Approved in 1993, it paved the way for cholinesterase inhibitor drugs, which are one of the two major drug types available in the market.

At present, 3 cholinesterase inhibitors (AChE inhibitors) – Donepezil, Rivastigmine, and Galantamine, and a N-methyl D-aspartate (NMDA) receptor antagonist, Memantine (which also acts as a dopamine antagonist), are approved as symptomatic treatments for use in AD ⁽⁸⁾.

The former prevents the enzymatic breakdown of acetylcholine, thereby increasing its levels in the brain. Acetylcholine is an important neurotransmitter that is responsible for memory and cognitive function in the brain. Memantine blocks glutamate from binding to its receptors. This prevents excessive excitotoxicity and neuronal cell death, which is thought to contribute to the pathogenesis of AD ⁽⁹⁾.

While these drugs slow down disease progression and delay symptom development, they do not significantly improve cognitive function or cure the disease. They also result in frequent side effects like dizziness, confusion, nausea, vomiting, diarrhoea, headache, weight loss, hypertension etc ⁽⁹⁾.

The Alzheimer’s disease diagnostics and therapeutics market was valued at USD 6,986.70 million in 2021, and it is expected to reach USD 9,639.23 million by 2027 with a CAGR of 5.51% ⁽¹⁰⁾. The major drivers of the AD diagnostics and therapeutics market include the increasing use of biomarkers and the rising prevalence of Alzheimer’s disease around the world ⁽¹⁰⁾.

New Horizons in Alzheimer’s Treatment

Amyloid plaques are the earliest manifestation of AD and may be detected as early as 20 years before the onset of symptoms(8). Several genetic, biomarker, and genome-wide association studies have implicated their role in the pathogenesis of both familial and sporadic AD. Research has shown that soluble Aβ oligomers are the key amyloid species responsible for neurotoxicity and disease progression in AD. Additional longitudinal amyloid and tau positron emission tomography (PET) imaging studies also demonstrated their role in downstream tau pathology and cognitive decline (11).

Aducanumab (commercially known as Biogen’s AduhelmTM) is the first drug to have been approved for Alzheimer’s treatment since 2003 (12). It is also the first drug in the market that targets the underlying pathology of the disease, rather than just the symptoms (11). It is a human monoclonal antibody that binds to aggregated Aβ with high affinity and promotes its removal by Fc receptor-mediated phagocytosis.

Aduhelm^TMhas been surrounded by controversy since its launch. In spite of phase 3 being stopped prematurely due to futility after an interim analysis, it was given accelerated approval by the FDA. Several members of the Peripheral and Central Nervous System Drugs Advisory Committee also resigned in protest of this decision.

The trials conducted for the efficacy and safety of Aduhelm^TM consisted predominantly of Caucasian participants, thus not including the people who bear a disproportionate burden of disease. Additionally, the cost of the drug is high, making it unaffordable for the majority of the population ⁽¹³⁾.

The drug also has several reported side effects ⁽¹⁴⁾ –

*Amyloid related imaging abnormalities (ARIA)

24% of subjects who demonstrated radiographic ARIA exhibited symptoms like headache, confusion, delirium, altered mental status, disorientation, dizziness, vision abnormality, and nausea ⁽¹⁴⁾.

As of December 2021 the FDA reported 2 deaths, including one participant who died due to serious ARIA.

In March 2022, Biogen produced over two years of Phase 3 data from two clinical trials for AduhelmTM at the International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2022). While the EMERGE trial found statistically significant changes in early AD, the ENGAGE trial did not meet its primary or secondary endpoints. However, a dose and time-dependent reduction in pathophysiological markers of AD was observed in both (16). Phase 4 trials are set to begin in May 2022.

Conflicting reports about the drug’s efficacy have made people wary about its use. A study involving over a thousand people was conducted by Zissimopoulos et al. (17) to measure self-assessed knowledge about Aducanumab amongst individuals aged 55 years and older. Results showed that despite concern about AD amongst 84.8% of the population, only 26.8% reported some or fair amount of knowledge of Aducanumab. While 43.8% agreed that Aducanumab would provide a societal benefit, approximately half of participants were concerned about costs. Overall, only 23.2% who said they would want to receive Aducanumab if they had Alzheimer disease. Individuals aged 60 to 75 years were less likely than those aged 55 to 59 years to desire treatment with the drug.

Conclusion

Incidences of AD have reached an all time high. At present, someone in the U.S. develops AD every 66 seconds. By 2050, experts speculate that a new case will be reported every 33 seconds ⁽¹⁾.

The accelerated approval granted by FDA to Aducanumab indicates that there is a dire need for newer treatment modalities for AD. Increased understanding of the pathophysiology of AD has led to the development and testing of many new agents.

One of the drugs currently under trial is Donanemab, a monoclonal antibody that can potentially decrease amyloid beta-plaque and slow the progression of Tau proteins in the brain. Another drug under development is Lecanemab, an anti-amyloid beta protofibril antibody ⁽¹⁸⁾.

In 2018, approximately 112 drugs for AD were in phase I, II, or III trials. While 63% of them were disease-modifying therapies (DMTs) aimed at beta-amyloid or tau proteins, 25% of the drugs in development were being tested for their ability to enhance cognition. The rest of the agents were intended to decrease behavioural symptoms such as agitation, apathy, and sleep disturbances ⁽⁹⁾.

Multiple trials are also currently in progress for the development of Alzheimer’s vaccine.

As many as 9 vaccines are under trial, with the first human trials started for an intranasal vaccine by Brigham and Women’s Hospital, Boston, Massachusetts using Protollin, an immunomodulator, to stimulate the immune system ⁽¹⁹⁾.

While all these promising treatment options are certainly in progress, the Aducanumab trials have raised some important questions – Are amyloid plaques really responsible for the cognitive decline in Alzheimer’s disease? Or are there other factors that come into play? The results of the trials suggest that it might be more prudent for researchers to look into the mechanism of ageing instead, and study the biological processes that go awry and lead to the development of Alzheimer’s.

References

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15. FDA Adverse Event Reporting System (FAERS) Public Dashboard. Available at: https://fis.fda.gov/sense/app/95239e26-e0be-42d9-a960-9a5f7f1c25ee/sheet/45beeb74-30ab-46be-8267-5756582633b4/state/analysis Accessed on: 15/04/2022

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17. Zissimopoulos J, Jacobson M, Chen Y, Borson S. Knowledge and Attitudes Concerning Aducanumab Among Older Americans After FDA Approval for Treatment of Alzheimer Disease. JAMA Network Open. 2022;5(2):e2148355.

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19. Brigham and Women’s Hospital, News Release, November 16, 2021.