Comment:
Realising the full potential of biomarker-informed clinical trials for neurodegenerative disorders

The recent approval of amyloid-targeting monoclonal antibodies for Alzheimer’s, following decades of failed trials, can be partially attributed to the development of improved biomarkers for patient screening and outcomes assessment.

For many neurodegenerative diseases, including Alzheimer’s, changes in the brain begin years before clinical signs of disease emerge. Clinical symptoms start out mild and nonspecific, gradually worsen, and vary between individuals.

Up to three in four symptomatic Alzheimer’s patients are misdiagnosed or undiagnosed in primary care.1 And, correct diagnosis often occurs late in disease progression after quality of life is impacted, when damage to the brain may be extensive, and possibly irreversible.²

Delayed diagnosis, misdiagnosis, and difficulty assessing changes in disease progression have all contributed to the exceedingly high failure rate of neurodegenerative disease clinical trials.

Importantly, the approved molecules for Alzheimer’s disease came from a drug class that was tested and failed 15 years prior.³

Instead of a drug discovery breakthrough, the successful Alzheimer’s trials were primarily distinguished from preceding failed trials because they employed biomarkers that allowed for the treatment of more correctly diagnosed patients earlier in their disease, and for the more sensitive assessment of treatment outcomes.

Buoyed by breakthrough technologies and methodologies that have enabled earlier intervention, Alzheimer’s drug developers are now at the forefront of adopting more nuanced, cost-effective and patient-centric clinical trial designs that have the potential to shift clinical development paradigms for the broader spectrum of neurodegenerative diseases.

For example, the AHEAD 3-45 study, one of the first trials to study a disease-modifying Alzheimer’s treatment in pre-symptomatic stage patients, is using recently developed blood-based biomarkers for patient screening.⁴

Blood-based biomarkers offer more accessible alternatives to traditional biomarker-based diagnostic methods, which relied on imaging machines or spinal taps, making it easier to test and recruit eligible trial participants.

Meanwhile, digital biomarkers, particularly wearable sensors, have exciting potential to collect data on cognitive function, motor symptoms, and other relevant disease features. This provides objective, continuous data, improving sensitivity and decreasing data variability. Wearables are most commonly used in neurodegenerative diseases with motor-based symptoms, such as Parkinson-type syndromes.

To determine the extent to which advances – including blood-based biomarkers, digital biomarkers and supporting innovations in trial designs – are being applied today, ICON surveyed 129 central nervous system (CNS) therapeutic developers focused on neurodegenerative disease.

Results showed near-universal adoption of biomarkers among today’s CNS developers, with 97 per cent of respondents reporting their use in clinical development. Of these, over half (56 per cent) used bio-fluid-based biomarkers that don’t require spinal taps; 57 per cent used biomarkers for patient screening; and 57 per cent used them for outcomes assessment. More than half of those who reported leveraging artificial intelligence indicated that they used it to accelerate biomarker detection (59 per cent).

However, the survey also suggested a continued opportunity for sponsors to ensure that biomarker-informed clinical trials are accessible, cost-effective, efficient, and aligned with regulatory requirements.

Addressing common challenges with biomarker-based screening

While recent biomarker innovations have enabled earlier and more accurate enrolment of patients with neurodegenerative diseases, implementing biomarker-based screening also has the potential to increase the cost, duration and inaccessibility of clinical trial recruitment.

This can occur if (1) eligible patients have limited access to screening, (2) the validity of biomarker-based screening varies by patient subpopulations, or (3) screen-fail rates rise.

To avoid exacerbating the recruitment and retention challenges of qualified, diverse patients faced by over 80 per cent of CNS developer survey respondents, the selection and adoption of biomarkers for patient screening must be strategic.

For instance, when using biomarkers in patient screening or assessment, developers must ensure they are equivalent across all eligible patient subpopulations.

This has proven to be a challenge in some Alzheimer’s clinical trials using amyloid-based inclusion criteria, in which lower average levels of amyloid in black patients resulted in much lower eligibility compared to white patients.⁵

Biomarkers, such as the ratio of plasma Aβ42/40, which has demonstrated more consistency across racial groups, may help streamline and accelerate the enrolment of representative patient populations.⁶

Meanwhile, non-traditional trial designs can help improve the feasibility of biomarker-based screening by accelerating patient recruitment and contributing to cost savings in clinical development. With less than a third of survey respondents using registries or non-interventional trials, these recruitment strategies are a surprisingly underutilised way to improve the drug development process for neurodegenerative conditions.

Studies, such as AHEAD 3-45, have demonstrated that recruiting from registries of trial-ready cohorts majorly accelerates enrolment of qualified patients, and is an enormous asset to clinical developers, especially those conducting trials in early disease patients or with biomarker-based eligibility requirements.⁴

If the resource requirements needed to support registry-based recruitment are too high, sponsors may benefit from considering alternative stepwise screening methods that may still provide pre-symptomatic, enrolment-ready cohorts at lower costs.

For example, in one still ongoing phase II study, the use of biomarkers to characterise and enrich the patient population in a stepwise screening process allowed a sponsor to save about US$2m by reducing site-based clinical assessments without sacrificing data quality.

Site and patient burden were first reduced through the initial pre-screening of medical records, which allowed patients with historic biomarker positivity to skip site-based blood testing. Then, those without historic biomarker positivity were first offered blood-based biomarker pre-screening on-site, so that the assessment of imaging-based biomarkers could be limited to patients with positive blood-based biomarker results.

Capitalising on the potential of biomarker-based outcomes assessment

Innovative technologies for outcomes assessment – particularly digital biomarkers – have the potential to accelerate and de-risk clinical development.

In particular, wearable sensors can collect data on cognitive function, motor symptoms and other relevant features of neurodegenerative diseases, providing continuous, objective data that enhances the sensitivity of outcomes assessment, reduces assessment variability and, crucially, minimizes the need for site-based clinical outcomes assessments.

In turn, the adoption of decentralised clinical trials (DCTs) can significantly reduce the overall financial, logistical and emotional burden on patients with neurodegenerative conditions – who disproportionately have mobility issues, travel constraints and/or strong preferences to remain in familiar environments – and their caregivers.⁷

Despite their advantages, fewer than a third of survey respondents reported using DCTs or hybrid elements in their clinical trials. DCTs are not feasible for every type of clinical trial. However, integrating decentralised elements into clinical trials should be possible for most.

Upfront challenges with adapting to new, hybrid or decentralised methods are likely to be outweighed by the value of more equitable access to clinical trials, easier recruitment and reduced drop-out rates.

Decentralised models can also allow for a scale of data collection that is otherwise impossible. For example, the largest randomised clinical trial ever conducted on Parkinson’s disease was enabled by in-home nurse visits. The Trial of Parkinson’s and Zoledronic acid (TOPAZ) plans to enrol over 3500 patients from throughout the US.⁸

Overall, sponsors of neurodegenerative clinical trials appear to have embraced the adoption of biomarkers for patient enrolment and outcomes assessment.

However, developers who are newly integrating biomarkers into clinical development may benefit from considering strategies to de-risk the selection of biomarkers and optimise their application in biomarker-based screening and outcomes assessment.

How these new technologies are implemented will ultimately determine whether they can fulfil their promise to accelerate and de-risk research and development across the full spectrum of CNS diseases.

References

1. Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer’s Association appropriate use recommendations for blood biomarkers in Alzheimer’s disease. ALZHEIMERS Dement. 2022;18(12):2669-2686. doi:10.1002/alz.12756
2. Dubois B, von Arnim CAF, Burnie N, Bozeat S, Cummings J. Biomarkers in Alzheimer’s disease: role in early and differential diagnosis and recognition of atypical variants. Alzheimer’s Res Ther. 2023;15(1):175. doi:10.1186/s13195-023-01314-6
3. Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2024. Alzheimer’s Dement Transl Res Clin Interv. 2024;10(2):e12465. doi:10.1002/trc2.12465
4. Rafii MS, Sperling RA, Donohue MC, et al. The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer’s disease. ALZHEIMERS Dement. 2023;19(4):1227-1233. doi:10.1002/alz.12748
5. Molina-Henry DP, Raman R, Liu A, et al. Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer’s disease trial. Alzheimer’s Dement. 2024;20(6):3827-3838. doi:10.1002/alz.13803
6. Xiong C, Luo J, Wolk DA, et al. Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals. Nat Commun. 2024;15(1):5539. doi:10.1038/s41467-024-49859-w
7. Howard L, Abdelnour C, Abner EL, et al. Decentralized clinical trials for medications to reduce the risk of dementia: Consensus report and guidance. Alzheimer’s Dement. 2024;20(7):4625-4634. doi:10.1002/alz.13891
8. Tanner CM, Cummings SR, Schwarzschild MA, et al. The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism. Npj Park Dis. 2021;7(1):1-6. doi:10.1038/s41531-021-00162-1