Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, cognitive impairment, and functional decline. The current competitive landscape in AD offers medications that are aimed at treating the symptoms of the disease. These drugs are modestly effective and primarily off-patent, creating significant opportunity for new entrants into the AD market.

Despite the FDA approval of Biogen’s Aduhelm (aducanumab) in 2021, when it was hailed as the first disease-modifying therapy (DMT) for AD, and the recent approval of Eisai/Biogen’s Leqembi (lecanemab) in January 2023, these new anti-amyloid-beta (Aβ) monoclonal antibody (mAb) DMTs are yet to become widely available to patients, and have not, as yet, had the impact on the AD market that was hoped. The US Centers for Medicare and Medicaid Services (CMS) limited the Medicare reimbursement of Aduhelm and subsequent similar products to only AD patients participating in randomised controlled trials due to limited efficacy data seen in Aduhelm’s pivotal Phase III trials, ENGAGE (NCT02477800) and EMERGE (NCT02484547). The decision has resulted in low uptake and poor sales for Aduhelm. As the CMS has not lifted the restriction for Leqembi based on data from its accelerated approval, the initial uptake of Leqembi will be impacted until there is a potential change in coverage, if full approval is granted for the drug.

Key opinion leaders (KOLs) previously interviewed by GlobalData indicated that due to the lack of widely available DMTs, the development of an agent that can reverse or stop the underlying pathology of the disease is the most important area of need in the AD space. Since AD is highly complex, there is still an incomplete understanding of the molecular pathophysiology of the disease, which means that there is no clear consensus on the mechanism of action (MOA) that has the highest potential as a curative therapy. This is reflected in the variety of MOAs with potential disease-modifying action present in the late-stage AD pipeline, with more than ten unique MOAs being targeted.

It is widely accepted that early pharmaceutical intervention is key to slowing or possibly halting the progression of AD. It is important to diagnose AD at its earliest stage to allow the current medications to achieve their maximum therapeutic effect. However, patients in many areas are still reluctant to seek a diagnosis due to the absence of curative therapies, making it hard to achieve high rates of early diagnosis. Thus, the need to develop effective DMTs is critical. Furthermore, the approval of new DMTs will open the possibility for biomarkers to be approved and reimbursed, allowing for easier earlier detection and diagnosis of AD.

As the focus of AD pharmacotherapy has shifted to the early stages of the disease, biomarker development has become an increasingly important area of unmet need. Biomarkers relating to brain imaging and cerebrospinal fluid (CSF) have been an important development for aiding the diagnosis of AD. However, there are issues surrounding their use. Biomarkers involving a magnetic resonance imaging (MRI) or positron emission tomography (PET) scans are very expensive and not widely available, and CSF biomarkers are highly invasive for patients as they involve a lumbar puncture. There is a great unmet need for simple, inexpensive, and non-invasive tests that could be applied on a large scale to screen for AD, as well as for the development of further non-invasive blood-based biomarkers that could have a big impact on the way AD is managed in the future.

Caring for AD patients can be difficult, especially as patients advance into the more severe stages of the disease. Patients with dementia are difficult to care for when agitated and are often prescribed antipsychotic medications and sedatives to alleviate behavioural issues, a practice that the FDA states can be dangerous in elderly patients. Given the prevalent off-label use of Risperdal and other antipsychotic medications for behavioural management in patients with dementia, drug development targeting these symptoms will provide more complete disease management and reduce caregiver stress.

A more diverse set of medication options must be made available, specifically those that can improve the control of other secondary symptoms associated with AD, such as agitation, hallucinations, delusions, depression, sleep impairments, anxiety and cognitive impairments. Offering such therapies would expand the AD drug market and could affect overall healthcare expenditures by improving medication compliance and preventing institutionalization. While there are several products in the late-stage AD pipeline targeting agitation associated with AD, including Lundbeck and Otsuka’s Rexulti (brexpiprazole), Avanir Pharmaceuticals’s AVP-786, Axsome Therapeutics’ Auvelity (bupropion + dextromethorphan), and Suven Life Sciences’ masupirdine, effective treatment options for the other secondary symptoms are likely to remain an unmet need.

Any new medication that can improve compliance or symptoms, maximize a patient’s independence, or prevent hospital or nursing home admission could have a massive clinical and economic impact. However, a novel DMT that can demonstrate significant efficacy in clinical trials could revolutionise the AD market in a way that the anti-Aβ mAbs have been unable to do thus far.