In World Alzheimer’s Month, expert Peter Schüler reflects on the potential implications of new Alzheimer’s therapies on the research landscape.
World Alzheimer’s Month offers an opportunity to reflect on the progress made in the search of effective treatments for this enormously burdensome disease and align our visions for the future.
This year, there is much progress to consider as we expect two further medicines, donanemab and lecanemab, to come to market.
These drugs offer more treatment alternatives to aducanumab as disease-modifying (DM) treatments in addition to the long-existing symptomatic therapies.
In addition to slowing the progression of the disease by 25-35% per year, the successful developments of these drugs provided some additionally encouraging results – namely that the countless disappointments in the past 20 years have led to valuable lessons learned which, in turn, helped to refine the methodologies for Alzheimer’s Disease (AD) drug development.
We have reached a hugely significant milestone in the long search for AD treatments: confidence in the research criteria for AD introduced by the National Institute on Aging and Alzheimer’s Association (NIA-AA).
Combined with the continuous optimisation of clinical endpoints such as CDR-SOB , population enrichment strategies by selecting those with an expected disease progression with the help of cognitive tests such as the Free and Cued Selective Reminding Test (FCSRT), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the use of biomarkers in the imaging and lab domain , these methods have all demonstrated value in the pivotal clinical trials.
This progress is worthy of celebration. And yet, these developments may have implications for those of us identifying next steps for clinical research in this area. Amyloid burden is just one aspect of the AD problem.
As such, there is still a high need for other treatments aside from newly available amyloid-targeting treatments. The fact that these treatments do not fully halt the disease further indicates that this part of the multifaceted pathophysiology is only representative of a minor portion of the disease spectrum.
Future research into the remaining 65-75% of disease progression could include other modes of action to achieve better symptomatic treatments, an earlier interference with the cascade from monomers via oligomers to the plaques, anti-tau strategies and further modes supporting neuronal survival. Someday, we hope to achieve restorative approaches.
As of August 2023, 496 trials are registered as planned or ongoing in the indication Alzheimer’s in Citeline.com. Of those, 328 are in early development phases 1 to 2/3 and 240 of those are sponsored by government or within the industry.
Among the 240 trials, thirty not yet approved modes of action are under development. As a result, we can expect more personalised combination therapies as we see established in other neuro-immunological diseases or in epilepsy. However, we can’t expect a magic bullet.
Implications of progress
Similar to what we see with the amyloid burden reducing treatments, any such new drug development will encounter a dark cloud hidden behind the silver lining that has emerged recently: more and more patients globally will benefit from the now available disease-modifying treatments, and consequently, less and less treatment-naïve patients will be available for the inclusion of coming clinical trials that could drive additionally meaningful therapies. This dilemma complicates clinical research.
New study protocols will need to consider ways to maintain patient centricity to support recruitment. For example, the “add on” approach allows approved therapies as a continued standard of care.
However, this will automatically flatten the slope of the progression curve, making it more timely and costly to show clinically relevant effect sizes in the future. Additional points of consideration include:
Recruitment of patients naïve to new disease-modifying trials
Access to the new treatments will differ by region, depending on the economic bandwidth of the healthcare system. Even in the US, it is anticipated that less than 10% of AD patients will qualify for the available DM therapies.
Specifically, those being apolipoprotein E (ApoE) positive may be reluctant to start a treatment which will not stop the progression but may create an additional problem via amyloid-related imaging abnormalities . Overall, the impact will not be immediate, but within the next 3-5 years it will change the research landscape.
New target populations
One of the lessons learned for the past DM therapy developments is the fact that earlier disease stages benefit the most. Thanks to cheaper and more convenient blood biomarkers, soon we may see the option to identify high risk candidates for AD who also may want to enroll in trials. We also have to allow a more diverse population to contribute to trials . Furthermore, this requirement should more be seen as an option, and indeed an opportunity, rather than as a burdensome requirement.
Patient centricity
Based on anticipated impacts to patient recruitment, future studies must be more patient-centric, i.e., patient-friendly, to be an acceptable alternative to more convenient approved treatments. This will include a concerted use of various tools we successfully used during the pandemic, including more home-based activities, telemedicine and phone-visits. Additional tools could include high frequency sampling, to be used to fully validate digital endpoints such as voice and speech analysis with computerised cognitive tests, and more context-related activity and sleep tracking to document the relevance of new treatments. As it stands, we will need to further improve our assessments to facilitate further use of these methods.
New applications
A convenient mode of application with expected high adherence to the therapy is making new compounds more attractive in a cognitively impaired population, e.g., patches or slow-release injections. This is also true in clinical development.
New endpoints
The FDA’s accelerated approval pathway now accepts surrogate or biomarker endpoints for conditional approvals. There is hope that even more disease-specific combinations of markers will suffice to gain full marketing authorisation. This would allow for shorter trials involving a smaller sample and thus facilitating further innovation.
New designs
Last though not least, the classic trial design may be replaced by concepts already established in other disease areas. For example, larger but simpler and mainly decentralised “add-on” therapies that utilise “time to event” as an endpoint or “add-on” platform designs with multiple active treatment arms running in parallel.
Planning for the future
In summary, even though the research landscape will see more enrolment hurdles due to available therapies in the mid-term, there is still room for novel treatment mechanisms and concepts. One also needs to consider that Alzheimer’s Disease is an endemic problem across the globe, with a high prevalence that continues to grow.
During World Alzheimer’s Month, we should celebrate the progress we have made in the pursuit of meaningful therapies, especially with recent breakthroughs.
However, we must remain steadfast in our efforts. Considering the implications above will help the clinical research industry identify eligible and interested populations to participate in future trials and bring more medicines to the patients and families affected by this disease, and that is certainly worth reflecting on this World Alzheimer’s Month.
Peter Schüler MD is senior vice president, drug development solutions at ICON.
