Are Australians living with dementia ready for new therapies?

Abstract

The Therapeutics Goods Administration (TGA) recently approved donanemab for the treatment of early symptomatic Alzheimer's disease (AD), which encompasses mild cognitive impairment (MCI) and mild Alzheimer's disease dementia (ADD).¹ A timely survey of memory clinic capabilities by Michaelian et al. in this issue of the Internal Medicine Journal highlights the significant challenges Australia faces to deliver this new therapy.²

Dementia is the most common cause of death in women in Australia and the second leading cause of death, and disease burden, overall. Over 411 000 Australians had a dementia diagnosis in 2023, and that prevalence will more than double by 2058.³

Specialist assessment of people with cognitive change is undertaken by geriatricians, neurologists and psychiatrists in health service-linked memory clinics or private settings. Cognitive and functional assessments facilitated by allied health, education, carer support, linkage to community supports and advice about related issues such as driving are provided. Diagnosis, management of comorbidities, mood and behavioural issues, lifestyle advice to preserve cognition and, where appropriate, trials of medication are undertaken.⁴ The increasing prevalence of dementia means that wait times for assessments are increasing, commonly more than 6 months in metropolitan centres and longer in regional and remote areas.

Pharmacological treatment of ADD has been limited to acetylcholinesterase inhibitors and memantine, which may provide symptomatic relief but don't affect the disease process. Most people with a diagnosis of ADD have a mix of neuropathologies, with pathognomonic amyloid beta (Aβ) plaques and neuronal tau tangles, combined with vascular change, alpha-synuclein inclusions and transactive response DNA binding protein 43.⁵ The ‘amyloid hypothesis’ has dominated research into AD and possible therapies: Aβ gradually accumulates over 10–20 years before a tipping point is reached where microglia are no longer able to ingest Aβ, and a proinflammatory state ensues with synaptic dysfunction, hyperphosphorylation of tau protein, destabilisation of microtubules, tangle formation and neuronal death. Cognitive symptoms arise at this point, progressing from MCI to mild ADD once impairment impacts on everyday functioning.⁶ Hypothetically, early detection and treatment might avert this cascade.

Many unsuccessful therapies aimed at Aβ, including monoclonal antibodies (mAbs), have been trialled. However, Phase III trials of lecanemab (CLARITY AD)⁷ and donanemab (TRAILBLAZER-ALZ2)⁸ reduced Aβ on positron emission tomography (PET) scans, improved markers of neurodegeneration in cerebrospinal fluid (CSF) and slowed cognitive decline. They are considered disease-modifying and have been approved for use in AD for MCI and mild ADD in several countries, including the USA, UK and Japan.

Both lecanemab and donanemab showed benefit in terms of slowing of decline using a variety of measures of cognition, functioning and quality of life. After 18 months of therapy, lecanemab-treated participants had declined by a relative difference of 27% less than placebo, and donanemab-treated participants declined 36% less, using the Clinical Dementia Rating Sum of Boxes (an 18-point scale assessing cognition and real-world function). However, the absolute difference using this scale between placebo and lecanemab was −0.45, and it was −0.67 for donanemab. This did not reach respective trial criteria for a minimal clinically important difference.⁹ Slowing of disease progression with donanemab compared to placebo amounted to a delay of 5.2 months to reach the same degree of impairment.⁶

Potentially serious harms include MRI-defined Amyloid Related Imaging Abnormalities (ARIA), in the form of cerebral oedema (ARIA-E) or haemorrhage (ARIA-H). The risk of ARIA is highest in the first 3 months of treatment. Most are asymptomatic, but therapy needs to be paused or halted depending on the severity of the reaction. Symptoms at any stage possibly due to ARIA require halting therapy and an unscheduled MRI. The incidence of ARIA with lecanemab was 12.6% (–E) and 17.8% (–H) and with donanemab it was 24% (–E) and 26% (–H). Being homozygous for apolipoprotein E ε4 (APOE ε4) gentoype greatly elevated the risk and is an exclusion for use in Australia. Treatment discontinuation rates were 6.9% with lecanemab and 13.1% with donanemab. Other significant adverse events included infusion reactions, stroke-like episodes and seizures. Mortality was 0.7% (CLARITY AD) and 1.9% (TRAILBLAZER ALZ2).⁶

There is a diversity of opinion regarding the current role of mAb therapies. Many consider that the benefits of slowing of decline and potential delay of the more severe stages of dementia outweigh the treatment burden, risks and costs. Adopting other measures of benefit such as ‘time saved’ with reduced carer burden have been suggested.¹⁰ Dementia researchers and support groups have strongly advocated for their use and funding.¹¹ Others see the absolute benefits as minimal and not justifiable if resources are taken from other areas of health expenditure.⁹ An approach that considers whether a treatment effect is clearly noticeable, valuable (e.g. important change in function) and worthwhile (e.g. value of change outweighs cost, side-effects, inconvenience) has merit for evaluating benefit.¹² Lecanemab and donanemab are approved for use in the UK, but are not publicly funded, deemed to have too little benefit to justify significant additional costs.

The TGA has rejected lecanemab twice due to marginal clinical benefit, especially for women and APOE ε4 homozygotes.¹³ mAb therapy is currently available in trials but is also increasingly being sought in private settings. Donanemab is not publicly funded and currently costs A$4700 per month full dose after 3 months' up-titration (approx. A$78 000 for 18 months treatment); costs for imaging, infusion and monitoring are additional.¹⁴ Patient-centred discussions to understand treatment criteria, risks, benefits, time commitments and (currently) cost will be essential.¹⁵

Treating ADD with mAbs is time and resource intensive. It requires confirmation of AD pathology by identifying Aβ either via a brain Aβ PET scan or by CSF analysis. Intravenous infusions bi-weekly for lecanemab or monthly for donanemab occur over 18 months. Donanemab is stopped once Aβ has been cleared, requiring another PET or CSF sample. Lecanemab is recommended to continue monthly. Baseline MRI scans are performed to exclude other pathologies and microbleeds suggestive of cerebral amyloid angiopathy. Four further MRI scans are performed to monitor for the development of ARIA.

The use of Aβ alone as a biomarker to predict dementia has been criticised given that not everyone with Aβ will develop dementia. The lifetime risk of ADD in a 65-year-old man with Aβ has been estimated at 21.9%, only 1.7 times higher than another with no Aβ.¹⁶ Better methods of targeting therapies to those at risk of progression are needed and are likely to involve a combination of biomarkers, imaging and cognitive testing.¹⁷

Efforts are under way in other countries to meet the challenges of introducing mAbs into care pathways.^{18, 19} Appropriate use criteria, based on trial inclusion/exclusion criteria, need adapting for individual health systems.²⁰ Estimates of the proportion of patients meeting eligibility criteria in real-world memory clinic populations are in the order of only 5%–8%.²¹ Significant implementation challenges include meeting the costs of the mAbs, neuroimaging capacity, CSF and APOE ε4 testing, expansion of infrastructure, staff, education and managing complications. Treatment and care pathways need redesign, including valid screening methods in primary care to identify people suitable for early assessment in memory clinics.¹¹

Michaelian et al. surveyed clinicians conducting memory clinics in Australia to understand the ability of memory services to introduce mAb therapies.² Clinicians were invited from 90 memory clinics registered with the Australian Dementia Network (ADNeT) and individual professional networks. Thirty responses were obtained predominantly from public memory services in metropolitan areas, with some private, regional and remote responses. Important findings included: only 40% of clinics use biomarkers (e.g. FDG-, Aβ or tau-PET); CSF and APOE4 testing was rarely done; and MRI was performed in about 60% of cases. Clinicians valued addressing other modifiable risk factors for cognitive decline such as hypertension and expected new therapies to show safety and meaningful benefit. Barriers to implementing mAb therapies included access and wait times for investigations, clinic capacity, staffing, infrastructure to provide infusions and monitoring. Education and a model of care encompassing appropriate use criteria, safety and monitoring were key need to be identified.

ADNeT estimates only 12 000 people attend memory clinics per year. If 8% meet eligibility criteria, about 1000 patients could be considered for mAb treatment. Current clinics would be overwhelmed to assess the estimated 250 000 new cases of MCI and ADD per year.²² Meeting this additional demand will require substantial expansion and investment in memory clinic infrastructure including specialist and support staff. Diagnostic support of MRI and PET imaging capacity, neuroradiologists and CSF biomarker analysis will be vital. MRI protocols and reporting require standardisation.²³ Genetic counselling regarding APOE ε4 status will be needed. Maintaining a Quality of Care Registry will be vital for monitoring safety and efficacy. Equity of access will be unlikely for many not connected to specialist centres, First Nations People, CALD background and those in regional areas. Current clinic structures are unprepared for this new demand.

The Australian Government released the National Dementia Action Plan (NDAP) in 2024 as a policy framework to improve the lives and care of people with dementia.²⁴ There are eight broad areas of action, with an initial three priority areas of risk minimisation; improving diagnosis and post-diagnostic care; and improving dementia data, maximising the impact of research and promoting innovation. Promoting risk reduction where there is a high level of evidence of benefit, such as controlling hypertension and promoting physical activity, may have a greater impact on minimising and delaying dementia. Strengthening the provision of diagnosis and post-diagnostic care for everyone with dementia is vital for an area already under-resourced and growing in need. Seventy-five per cent of people with dementia are aged over 75 and are best managed by multidisciplinary services to provide comprehensive care of comorbidities.³

AD research is rapidly evolving and imminent developments may soon clearly favour disease modifying therapies. Ongoing data collection from real-world use of mAbs in the USA is showing reassuring safety. Costs may be reduced using plasma biomarkers such as tau phosphorylated at threonine 217 for detecting Aβ and could obviate the need for CSF or Aβ PET scans but have yet to be approved in Australia.²⁵ Trials of subcutaneously administered mAbs also show promise but would still require MRI monitoring. Data on the durability of benefit and delayed transitions to more severe stages may demonstrate cost effectiveness.¹¹ Prospective trials with mAbs are under way in asymptomatic ‘at-risk’ people with amyloid, which, if positive, may favour early detection and treatment. Other non-amyloid therapies including anti-tau antibodies and various modulators of neuroinflammation may significantly change treatment pathways.⁶

We look forward to the implementation of the NDAP with robust promotion of evidence-based dementia risk-reduction strategies and improved care pathways. Expanding capacity to meet future needs should include the ability to provide cost-effective disease-modifying therapies for those likely to benefit, as well as enhancing the provision of care along the entire dementia journey for all.