The research landscape is littered with failures in the search for treating Alzheimer’s disease. For decades, we’ve seen high-profile therapies advance in the clinical trial realm only to yield disappointing results in Phase 3 trials. But as populations age around the world and the costs of caring for Alzheimer’s patients grow, pharmaceutical companies and regulators must take notice of build off the momentum we are seeing with new therapies. They need to stay committed to research and development, as well as bolster an infrastructure that opens access to more patients.
Research showing that the drug lecanemab slowed cognitive decline is a major milestone and further supports the argument that therapies targeting amyloid plaques in the brain present a path forward. We believe regulatory approvals for new therapies with blockbuster potential are imminent and will represent the first step in major societal changes to the way we think about and treat dementia.
Scale of the Problem
Alzheimer’s disease is the most common and well-characterized form of dementia, accounting for 60-80% of cases. It typically presents with memory problems and is differentiated from other forms of dementia by two hallmarks in the brain: β amyloid neuritic plaques and phosphorylated tau neurofibrillary tangles. In the absence of targeted treatments, most patients with typical presentation will never receive a definite diagnosis.
Today, upwards of 55 million globally live with dementia. Predictions suggest that number will more than double to 139 million by 2050. This is primarily due to aging populations around the world. Since age is the primary risk factor for dementia, the more elderly populations grow, the more cases of dementia occur.
Dementia is also the 7th leading cause of death worldwide, causing 1.6 million deaths in 2019. Even more strikingly, this figure is growing rapidly, making dementia the number one fastest growing cause of death worldwide.
Cost to Society
All these cases and deaths come at a financial cost — a staggering $1.3 trillion in 2019 when you look at direct and indirect costs. To put that in context, it’s similar to the entire worldwide pharmaceutical industry, or the gross domestic product of Spain.
Increasing costs of care mean that total costs will grow faster than prevalence. Furthermore, annual per-patient costs increase with disease severity, meaning that aging populations reaching later stages of dementia are putting additional strain on the system. As a result, the global cost of dementia is predicted to reach $2.8 trillion by 2030.
Slow Progress on Treatments
Treatment of Alzheimer’s disease currently involves managing patient symptoms and wellbeing. No widely used therapies can prevent or slow down disease progression, but several drugs targeting cognitive symptoms can reduce or stabilize a patient’s condition for a limited timeframe. These include cholinesterase inhibitors such as donepezil or the glutamate regulator memantine, all of which were first approved around two decades ago.
Since the cholinesterase inhibitors were approved, there have been numerous attempts to target disease progression with novel therapeutics. However, the failure of largescale Phase 3 clinical trials, often following mixed signals in Phase 2, has become a regular occurrence. Most recently, Roche announced plans to halt trials involving gantenerumab. The anti-amyloid antibody failed to meet the primary endpoint in the two Graduate trials.
Things are About to Change
Despite frequent failures, a glimmer of hope is emerging. The Food and Drug Administration in 2021 awarded accelerated approval to the first disease-modifying drug for Alzheimer’s disease, aducanumab. The approval was not without controversy, given the data it was based on was less than solid, but nonetheless the decision left the door ajar for further approvals based on surrogate biomarker data. Where aducanumab fell down was in gaining market access, as the Centers for Medicare and Medicaid Services took the unprecedented decision to deny access for Medicare patients unless enrolled in an approved randomized clinical trial.
The next anti-amyloid antibody on the radar is lecanemab, which is being advanced via a 50/50 profit share between Biogen and Eisai. Top-line results, unveiled at the recent Clinical Trials on Alzheimer’s Disease conference in San Francisco, as well as in the New England Journal of Medicine, were surprisingly positive – the drug reduced clinical decline by 27% versus placebo at 18 months in the primary endpoint, and met several other key secondary endpoints. Despite questions about the drug’s safety in relation to its overall benefit, this is still considered much stronger data than was presented for aducanumab, and the drug is expected to gain access, at least in the US. In fact, following this announcement, analysts are projecting peak year sales for lecanemab over $5 billion.
Lecanemab will be closely followed by two further anti-amyloid antibodies from Eli Lilly, donanemab and remternetug, which could launch as early as 2023 and 2025, respectively. Eli Lilly reported that donanemab reduced amyloid plaques by 65% after six months. Similar to lecanemab, the therapies are expected to compete for uptake over the next decade, with factors such as ease of administration affecting market dynamics.
Other Trends to Watch
While we expect imminent approval of one or more novel therapeutics, there are several reasons not to hold your breath. Further study to dissect safety issues is required. Understanding the best way to administer these therapies and building a sustainable diagnostic infrastructure to ensure patient access also have to be addressed. Change takes time. And we can’t lose sight of the fact that the healthcare ecosystem is interconnected. There are several other important trends worth watching, simultaneous to drug development:
1. Improving awareness and understanding of dementia
Stigma surrounding dementia is still a major barrier, both to patients and families seeking treatment and healthcare practitioners taking the disease seriously. More than 60% of healthcare practitioners surveyed by the London School of Economics and Political Science said they believe dementia is a normal part of aging, and 33% believe there is little point in a diagnosis. The approval of novel therapeutics alone is expected to help increase awareness of dementia as a treatable disease. However, the pharmaceutical industry can help further speed this along by supporting targeted awareness campaigns and educational support programs for patients, caregivers, and clinicians.
2. Increasing focus on diagnostic approaches
It is estimated that only 25% of dementia cases are diagnosed, limiting the size of the opportunity for novel therapeutics. Current guidelines recommend structural imaging for all suspected cases (mainly to rule out other treatable causes of dementia), but specialized tests that can identify amyloid pathology (such as amyloid PET imaging or CSF tests) are only used in unusual cases. In coming years, we can expect to see scientific improvements, such as the ability to detect amyloid in blood rather than CSF, avoiding the need for an invasive lumbar puncture. As the new amyloid-targeting therapies are likely to have confirmed amyloid pathology as a prerequisite, the development of companion diagnostics may aid market access and price negotiations.
3. Emerging approvals of digital therapeutics
Digital therapeutics have already been approved in the field of neurology, such as software for treating insomnia or ADHD. Now, companies such as Brain+ and Cognito Therapeutics are investing in developing digital therapeutics for Alzheimer’s disease. These either digitize already accepted disease management techniques, such as cognitive stimulation therapy, or provide a non-drug avenue to explore potentially disease-modifying approaches. Either way, combination approaches with novel pharmaceuticals may lead to meaningful and cost-effective improvements in patient outcomes and ultimately broader uptake.