Why Industry Must Design Alzheimer's Trials To Include People With Down Syndrome

By Andrea Pfeifer, AC Immune S.A., and Michael Rafii, Keck School of Medicine, University of Southern California

People with Down syndrome (DS) have long been excluded from clinical trials and neglected in the development of new therapies, leaving them without equitable access to new treatments. Recruitment of people with DS involves special challenges, but these challenges can be addressed with planning and education. In some indications, clinical trials including people with DS may even provide the optimal path toward proof of principle.

AC Immune S.A. is one of the few companies to take on this particular challenge in Alzheimer’s disease (AD). It's currently conducting its second study in DS-associated AD (DSAD). Its ABATE study is testing an anti-amyloid immunotherapy candidate that can potentially delay or prevent the onset of AD by teaching the body’s immune system to clear pathogenic forms of the beta amyloid protein.

While the challenges and solutions for recruiting people with DS in clinical trials vary depending on the disease and treatment being studied, our experience in DSAD illustrates how sponsors can take the steps necessary to fulfill their ethical obligation to improve the health of all the patients living with the conditions they seek to treat.

Why Alzheimer’s Disease?

Alzheimer’s pathology occurs in all individuals with DS by age 40, leading to a 95% risk of dementia by age 70.¹ Because life expectancy in DS has climbed, there are now more adults with DS living with AD, often in the care of now-elderly parents or adult siblings. Consequently, AD is now the leading cause of death in adults with DS.²

While DSAD is very similar to other forms of AD, there are key differences. The disease develops earlier and progresses faster in people with DS than in the general population.³ In addition, in DSAD, the accumulation of amyloid beta plaques in the brain is driven by the excess production of amyloid beta caused by an additional copy of the amyloid precursor protein gene, which resides on chromosome 21.

Given the high risk of AD in people with DS, the FDA’s July approval of a third antibody therapy shown to slow disease progression should be cause for celebration. Yet there was a critical missing factor in the clinical development programs for AD antibody treatments — none of them included people with DS.

AD Trials Exclude People With DS — And Leave Their Needs Unmet

The exclusion of people with DS from AD therapy trials leaves patients and families to make care decisions, like choosing a medication, without any evidence of efficacy and safety. Their exclusion from trials in turn creates barriers to the greater DS population’s treatment.⁴ Some classes of AD therapeutics, such as  N-methyl-D-aspartate (NMDA) antagonists, are less effective in DSAD than in sporadic AD. ⁵

Additionally, the lifelong accumulation of amyloid in the brains of individuals with DS raises theoretical but serious concerns about the risk of adverse events associated with anti-amyloid antibodies, such as amyloid-related imaging abnormalities (ARIA).⁶ A recent study in the Journal of the American Medical Association (JAMA) lends further weight to that concern because it showed in a postmortem assessment that the anti-amyloid antibody lecanemab had bound extensively to blood vessels in brain tissue from 15 people with DS.⁷ Current treatment guidelines developed by the Alzheimer’s Disease and Related Disorders Therapeutics Work Group for anti-amyloid antibodies recommend withholding treatment of individuals with DS until safety studies with lecanemab are conducted in this population.⁸

Ethics and equity demand that this vulnerable population be included in clinical trials of new therapies to treat AD. At the same time, the genetic basis of DSAD, in contrast to sporadic AD, provides a unique opportunity to demonstrate proof of principle for anti-amyloid therapies that have preventative potential. People with DS experience a uniformly highly predictable disease onset and rapid progression (due to the extra copy of chromosome 21), reducing the inter-person variability that can confound efficacy analyses and potentially reducing the length and size of proof-of-concept studies as compared with studies conducted in people with sporadic AD.

Capitalizing on that opportunity and closing the gap in evidence and access to care for people with DS requires designing clinical trials adapted to the population's unique requirements.

Special Considerations For AD Trials Including People With DS

People with DS have a range of co-existing medical conditions, such as epilepsy or seizures, stroke, and sleep apnea, that vary from one person to the next.⁹ They also have intellectual disability that varies in severity across the population. Both of these factors complicate the design and execution of clinical trials aimed to include them.

Intellectual Disabilities

Intellectual disability necessitates adapting clinical and cognitive endpoints used to assess efficacy. In DSAD trials, the assessment scales used to measure memory and cognition are different from those used in AD trials for the general population.¹⁰ Specifically, individuals with DS tend to score very low on cognitive tests that were developed for use in the general population, even if they do not have dementia. These floor effects may limit the feasibility of many cognitive instruments used to assess longitudinal change in memory or the impact of a particular drug on this change. Few empirically evaluated, psychometrically sound outcome measures appropriate for use in clinical trials for individuals with DS have been identified.¹¹

The differences in baseline cognition require either a separate study or a prospectively designed cohort for participants with DS. In addition, it is challenging to find appropriate sites because only a limited number have the required expertise to recruit individuals with DS into an AD study.¹²

Intellectual disability also complicates the informed consent process and creates challenges in creating study brochures, flyers, fact sheets, websites, and other patient materials. To address these issues in AC Immune’s AD studies, we have created unique supporting materials to ensure that individuals with DS can understand and interpret the complex information necessary to provide truly informed consent. One example is a series of presentations designed with input from DS patient groups to help investigators describe ABATE to potential volunteers in language that is easy to understand for people with intellectual disability.

Educational materials and accommodations may be needed to assist with imaging assessments, such as PET scans and MRI, which may be difficult for people with DS to undergo due to claustrophobia or difficulty remaining still.

Younger, More Active Lifestyles

Another unanticipated challenge in testing an AD therapy in people with DS is that the burden of participating in the study is a bigger factor than with sporadic AD. In the latter setting, trials typically recruit people aged 50-85 who are experiencing some degree of dementia or cognitive impairment. In the setting of DS, earlier onset leads to recruiting much younger people with more active lives.

For the ABATE study, participants with DS are typically 35-50 years of age and do not have dementia. They are healthier and more active than people with sporadic AD. They may still be in the workforce as well. Recognizing the younger age and respecting the different aspects of the lives of study participants with DS, we can hopefully enable them to view participation in the study as a way to support their futures.

Caregiver Trust

Being sensitive to the concerns of those seeking to protect vulnerable individuals with DS, we have adapted clinical trial procedures to increase the confidence and trust of caregivers and families, who are often highly protective of individuals with DS due to concerns about potential health or safety risks. In addition, differences from one region to another in regulations and legislation that seek to protect people with intellectual disabilities from abuse can inadvertently create obstacles for research that includes people with DS.

Getting Support For Solutions

Our efforts to remove the barriers to including people with DS in clinical trials, combined with support from expert advisors, demonstrate that the challenges can be mitigated or overcome.

It is essential to consult with KOLs who have experience with research in and care of people with DS. Choosing an expert to be the coordinating investigator will help ensure that the scientific design is robust and that the protocol considers the needs of the DS population.

The ABATE study protocol includes two prospectively defined cohorts: one for adults who do not have DS and do have mild cognitive impairment (MCI) and one for adults with DS who do not have dementia. To reassure regulators and investigators of safety, the DS cohort was opened only after interim safety results had first been obtained from the MCI cohort.

This cautious, stepwise approach also provided reassurance to potential participants with DS and their caregivers — and these are among the most important experts to be involved in developing and recruiting trials in DS.

For ABATE, individuals with DS and caregivers reviewed the informed consent alongside experts in the research and treatment of DSAD. The individuals with DS and caregivers advised developing additional preliminary materials to be used before the informed consent process. Patient advocacy groups and families that include people with DS also advised on materials including a website, posters, brochures, webinars, and presentations.

ABATE is continuing to recruit patients across 14 sites in the U.S., U.K., and Spain. Patient advocacy groups in each of the ABATE study’s countries also ensured that communications were culturally appropriate to the DS communities where the study is being conducted.

With the continued advice and support of patients, advocacy groups, caregivers, and KOLs, completion is expected in 2026. We hope it will be the first of many more trials in this all too often neglected population.

References:

1. Fortea J, Vilaplana E, Carmona-Iragui M, et al. Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet 2020; 395: 1988–97.
2. Fortea J, Zaman SH, Hartley S, Rafii MS, Head E, Carmona-Iragui M. Alzheimer’s disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol 2021; 20: 930–42.
3. Wisch JK, McKay NS, Boerwinkle AH, et al. Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer’s disease: a cross-sectional study. The Lancet Neurology 2024; 5: 500-510.
4. Rafii MS, Fortea J. Down syndrome in a new era for Alzheimer disease. JAMA 2023; 330: 2157–58.
5. Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke TA, Goldson EJ, Costa AC. Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl Psychiatry 2012; 2:e141.
6. Carmona-Iragui M, Balasa M, Benejam B, et al. Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer’s disease. Alzheimers Dement. 2017; 13:1251-1260.
7. Liu L, Saba A, Pascual JR, et al. Lecanemab and vascular-amyloid deposition in brains of people with down syndrome. JAMA Neurol. Published online August 19, 2024, at https://jamanetwork.com/journals/jamaneurology/article-abstract/2822642.
8. Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis 2023; 10: 362–77.
9. Baksh RA, Pape SE, Chan LF, Aslam AA, Gulliford MC, Strydom A. Multiple morbidity across the lifespan in people with Down syndrome or intellectual disabilities: a population-based cohort study using electronic health records. Lancet Public Health 2023; 8: e453–62.
10. Rafii MS. Alzheimer's disease in Down syndrome: Progress in the design and conduct of drug prevention prials. CNS Drugs 2020; 34(8):785-794.
11. Krinsky-McHale SJ, Hartley S, Hom C, et al. A modified Cued Recall Test for detecting prodromal AD in adults with Down syndrome. Alzheimers Dement (Amst) 2022; 14(1):e12361.
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About The Authors:

Andrea Pfeifer, Ph.D., cofounded AC Immune SA in 2003, serving as CEO and member of the Board of Directors. She successfully led the company’s NASDAQ IPO in 2016. She was previously head of Nestlé Research Centre in Lausanne, Switzerland, where she played a major role in connecting science and business. She is a key member of the CEOi initiative on Alzheimer’s disease and the Davos Alzheimer’s Collaborative (DAC). Pfeifer holds a Ph.D. in toxicology (cancer research) from the University of Würzburg, Germany, and is a registered toxicologist and pharmacist.

Michael Rafii, MD, Ph.D. is a physician-scientist whose research focuses on developing new treatments for AD, including a genetic form of AD that occurs in people with DS. He is the principal investigator of the NIH-funded Alzheimer’s Clinical Trials Consortium – Down Syndrome (ACTC-DS), where he leads several clinical trials across an international network of academic research sites. Rafii is the medical director of the Alzheimer’s Therapeutic Research Institute (ATRI) and professor of clinical neurology at the Keck School of Medicine at the University of Southern California.