Recently, researchers at King’s College London published a study in Translational Psychiatry on a feedback loop underlying brain degeneration in Alzheimer’s disease (AD) that, they suggest, may be the reason so many clinical trials targeting this disease have failed.
In this new study, the researchers found that when amyloid beta (Abeta) destroys a synapse, the nerve cells produce more Abeta, leading to further destruction of synapses. The researchers hypothesize that once this feedback loop becomes dysregulated, it is too late for drugs which target Abeta to be effective. In addition to explaining the failures of many AD trials, the researchers believe their discovery underscores the importance of early therapeutic intervention in this devastating disease.
The researchers also identify a clinically approved drug — fasudil — which appears to break the cycle and protect against memory loss in animal models of Alzheimer’s. Fasudil targets a protein called Dickkopf-1 (Dkk1), which stimulates the production of Abeta. Notably, in humans, Dkk1 is barely detectable in the brains of young adults, but its production increases with age. In this study, after two weeks of treatment with fasudil, mice engineered to develop large deposits of Abeta in their brains with age demonstrated a dramatic reduction in Abeta deposits.1
While this approach to disrupting the cycle of Abeta production rather than targeting Abeta itself is innovative and opens a potential new pathway for Alzheimer’s clinical research, we foresee a number of challenges to the clinical development of fasudil as an AD drug.
Abeta in AD
A progressive neurodegenerative disease characterized by memory loss, cognitive impairment, and functional decline, AD affects approximately 5.7 million Americans and around 44 million people worldwide. These numbers will almost double every 20 years, reaching 75 million in 2030 and 131.5 million in 2050. People with severe AD require constant observation, resulting in a drastic reduction in quality of life for both patients and their caretakers.
In AD, Abeta-rich plaque deposition occurs in the open regions of the brain caused by atrophy.4 Abeta is formed from the amyloid precursor protein (APP). In a healthy brain, APP is cleaved by three enzymes: alpha, beta, and gamma secretase. Alpha secretase cleaves APP at a site that prevents formation of Abeta, while beta and gamma secretase contribute to Abeta production.
The amyloid hypothesis posits that processes governing production, accumulation, or disposal of Abeta are the primary cause of AD. Overproduction of Abeta has been linked to development of AD, but, to date, a number of drugs targeting Abeta have failed in clinical trials.
Merck terminated its study of verubecestat, a beta-site APP cleaving enzyme (BACE) inhibitor which blocks an enzyme involved in the production of Abeta, in February 2017. In May 2018, Johnson & Johnson stopped mid-stage trials of its BACE inhibitor, atabecestat, after investigators observed serious elevations of liver enzymes in some study participants.3 Shortly after, in June 2018, Astra Zeneca and Eli Lilly terminated their Phase III clinical trials of lanabecestat, yet another BACE inhibitor. The pharmaceutical partners opted to stop their AMARANTH (NCT02245737) and DAYBREAK-ALZ (NCT02783573) trials after an independent data monitoring committee concluded they were unlikely to meet primary endpoints based on an interim analysis.
The accumulated failures of BACE and Abeta inhibitors, including monoclonal antibodies and gamma secretase inhibitors, have revived doubts about the Abeta hypothesis. Although the translation of animal models of AD to humans has limited predictive value, a systematic review of the relationship between Abeta and measures of cognitive deficit in transgenic mice showed no significant difference in cognitive performance between mice with elevated levels of Abeta and those with normal levels.
In human studies, Eisai and Biogen reported that while their BACE inhibitor, E2609, could lower Abeta, it failed to significantly improve AD symptoms.6 It is also important to keep in mind that, because Abeta is present not only in plaques but also in blood vessels in the brain, there is a limit to the dosing of amyloid-removing agents due to the risk of cerebral edema (ARIA-E) or even cerebral hemorrhage (ARIA-H).
The future of AD treatment development
Among the leading causes of death, AD is one of the few conditions that cannot be prevented, cured, or even significantly slowed. Despite intensive research, nearly 15 years have passed since the last new Alzheimer’s medication was approved, and the AD clinical trial failure rate of 99.6 percent is the highest of any therapeutic area.
According to a pipeline analysis presented at the Alzheimer’s Association International Conference in London in July 2017, the development timeline for disease-modifying therapies after pre-clinical development and initial characterization is approximately 13 months for phase I, 28 months for phase II, and 51 months for phase III, followed by a regulatory review period of 18 months. As a result, the total development timeline for an AD drug, including pre-clinical development, may be more than nine years. Given the long development lifecycle, it is critical for companies to take into account mechanisms of action and clinical trial designs when estimating the probability of success of their AD therapeutic candidates.
The Abeta hypothesis has been the primary target for disease-modifying therapies for over 20 years, but more recently, the focus of research has shifted to tau-targeted therapies. We have also seen a shift in the stage of AD being studied in clinical trials. With advances in our understanding of the underlying anatomical and pathophysiologic changes which precede the onset of clinical symptoms, research and development have begun to focus on mild cognitive impairment (MCI) or even prodromal AD. Even this may be too late in the disease course — the current scientific view is that, by the time an individual becomes symptomatic, irreversible neuronal damage has already occurred.
Of the 143 Alzheimer’s trials active as of July 2017, fifty-one are targeting healthy, healthy at-risk, or MCI to mild AD patients, including 21 studies focused on completely asymptomatic individuals.7 Studying investigative drugs in asymptomatic individuals who have an increased risk of AD requires long-term studies in large patient populations. It also requires that the investigational drug has an excellent safety profile and an expected-to-be-significant benefit-risk ratio as study participants who are otherwise healthy will be exposed to the investigational drug over several years. As an example, the recently-terminated Johnson & Johnson study of atabecestat was a more than 1,500-patient trial planned over four to five years.
The lengthy duration of AD studies in healthy, at-risk subjects also presents a challenge to recruitment and retention, which requires sponsors to adopt new approaches to conducting clinical trials. Other issues that need to be factored into study design are:
- The hard-to-predict conversion rate of at-risk subjects into AD, which affects sample size calculation and study duration
- Long-term safety
- Other or currently unknown factors that influence the progression of normal aging into AD
Clinical trials in AD often struggle to find ways to separate out symptomatic effects of potential agents from disease-modifying effects. Clinical trial designs have been developed to try to adjust for symptomatic effects and allow clinical rating scales to be used as endpoints. For example:
- Wash-in analyses, which compare the change between groups in clinical outcome measures over the first few weeks or months of a study to identify early symptomatic effects
- Wash-out analysis/staggered withdrawal, where treatment is withdrawn from both the active agent- and placebo-treated groups at the end of the study
- Randomized staggered start/delayed-start, in which one group of patients is randomized to receive the investigational agent from the start of the study while the second group is randomized to receive placebo for an initial period before being given the investigational agent
- Futility, a type of study which compares the outcome of a single treated group against a pre-determined threshold value reflective of a clinically meaningful change
- Long-term follow-up trials, where disease modification is inferred from sustained divergence in outcome measures between groups over time
- Adaptive design, which can help minimize the overall sample size and duration of a study by stopping recruitment early in response to strong signals of success or futility based on interim analysis
Sponsors should keep in mind that each of these study designs has limitations which may make it difficult to draw conclusions about an agent’s disease-modifying properties.
As we look to the future, we expect to see trends that will transform the overall approach to AD clinical trials, bridging the gap between research and clinical care. Careful consideration and optimization of the clinical trial experience for participants and caregivers is an essential component of study planning, and studies will need to be optimized for study duration, population size and endpoints to demonstrate disease-modifying effects. For assistance with designing and executing your AD clinical trial, contact us today.
 Elliott D, et al. A role for APP in Wnt signaling links synapse loss with β-amyloid production. Translational Psychiatry 2018;8(1).
 Alzheimer’s Disease International. Dementia statistics. Available at https://www.alz.co.uk/research/statistics.
 Reuters. Johnson & Johnson scraps Alzheimer’s trials on safety concerns. Published May 18, 2018. Available at https://www.reuters.com/article/us-johnson-johnson-study-alzheimers/johnson-johnson-scraps-alzheimers-trials-on-safety-concerns-idUSKCN1IJ2BC.
 Alzheimer’s Association. Beta amyloid and the amyloid hypothesis. Available at https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf.
 Merck. Merck announces discontinuation of APECS study evaluating verubecestat (MK-8931) for the treatment of people with prodromal Alzheimer’s disease. Published February 13, 2018. Available at https://investors.merck.com/news/press-release-details/2018/Merck-Announces-Discontinuation-of-APECS-Study-Evaluating-Verubecestat-MK-8931-for-the-Treatment-of-People-with-Prodromal-Alzheimers-Disease/default.aspx.
 Drug Development Technology. Another BACE inhibitor fails in phase III trials. Published June 20, 2018. Available at https://www.drugdevelopment-technology.com/comment/another-bace-inhibitor-fails-phase-iii-trials/.
 Foley AM, et al. Systematic review of the relationship between amyloid-β levels and measures of transgenic mouse cognitive deficit in Alzheimer’s disease. J Alzheimers Dis 2015;44(3):787-795.
 Us Against Alzheimers. Alzheimer’s Drugs in Development Pipeline, released July 2017. Available at https://www.usagainstalzheimers.org/sites/default/files/alzheimers-drugs-development-pipeline-2017.pdf.
 McGhee DJM, et al. A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer’s disease and Parkinson’s disease. BMC Neurol 2016;16:92.