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S16: Is Clinical Trial Design a Barrier to Alzheimer’s Disease Pharmacotherapy Development? An Analysis Based on Drug Class

Poster Presenter

Tyler Yoshito Fukunaga

PharmD and MS Regulatory Science Candidate 2023
University of Southern California
United States

Objectives

The objective of this study is to identify common issues and elements of clinical trial (CT) design among prominent Alzheimer’s Disease (AD) drug classes that have unsuccessful drug development within this disease state and suggest improvements for clinical development moving forward.

Method

Clinical trial data of phase II and III AD drug candidates from 2015 to 2020 was collected from clinicaltrials.gov. The four most prominent drug classes: amyloid beta (Aß) modulators, BACE inhibitors, neurotransmission enhancers, and anti-inflammatories were analyzed based on clinical trial design.

Results

Within the timeframe of 2015-2020, 29.3% (n=41) of Phase II and III CTs testing drugs for treatment of AD met endpoints where no Phase III study successfully met endpoints. Most trials testing the amyloid beta modulators (71.4%), BACE inhibitors (80.0%), and neurotransmission enhancers (100%) did not meet endpoints; surprisingly, however, many of the trials testing anti-inflammatories (75.0%) met endpoints. All amyloid beta modulator trials (n=14) shared a concerning design feature: the late initiation of treatment in patients 50 years of age and older, an age which is thought for AD to be irreversible through amyloid beta modulation. Four trials met endpoints despite late initiation of treatment; however, these were phase II studies mainly testing for safety and efficacy on biomarkers. On the other hand, 90.0% of the trials that did not meet endpoints failed due to a lack of significant improvement in cognition. All BACE inhibitor trials (n=5) reported no improvement or worsening of cognition in treatment groups. Since BACE is an upstream modulator of amyloid beta, the initiation of treatment in patients 50 years of age and older in all the trials was once again a concerning trial design feature. However, 100% (n=4) of the unsuccessful trials used appropriate biomarker outcomes to support the proposed efficacy. Neurotransmission enhancing drugs were the most prominent class of AD therapeutics that failed to produce a single successful trial in 2015-2020. A concerning study design feature of all the trials was the absence of biomarker endpoints in all four trials. Anti-inflammatories, unlike any class of AD therapeutic from 2015-2020, experienced the most success with 75.0% of trials meeting endpoints. Interestingly, a common design feature shared amongst the trials that met endpoints (n=3) was the use of fewer than 50 participants whereas the trial that did not meet endpoints used a patient population of 161 participants.

Conclusion

While most attribute the failure of AD drug development to the lack of understanding of the disease’s complex biological pathways and pathogenesis, there are clearly aspects of CT design that can be modified to better facilitate the development of AD drugs. Due to the unique mechanism of action of each class of AD drugs, it is important to design CTs to best assess the drug’s mechanism of action. Aß modulators and BACE inhibitors demonstrated successful target engagement through significant differences in biomarker outcomes in treatment versus placebo groups. However, this effect did not translate into an improvement in cognition in treatment versus placebo groups. A possible explanation for this discrepancy could be the late initiation of treatment at an age where AD is irreversible. Aß modulator treatment could be initiated in younger patient populations; however, the viability of such long-term studies is questionable. Neurotransmission enhancing drug trials did not incorporate biomarker outcomes into any of the trials from 2015-2020. These trials could incorporate simple biomarker measurements such as quantifying neurofilament (a biomarker of neurodegeneration) or MRI/CT scans to demonstrate target engagement and proof of concept prior to cognition measurements. However, failure to improve cognition in all neurotransmission enhancing drug trials may signal a deeper issue. Due to the “general” neurotransmission enhancing effects of these drugs, adjunctive therapy to another class of drug may be considered. Anti-inflammatory trials may overlook the trial design feature of patient population size, as trials that tested anti-inflammatories and met cognitive endpoints consisted of fewer than 50 patients. Smaller population sizes may allow clinicians to more accurately rate cognition than in trials with hundreds to thousands of participants. Future research is necessary to explore the relationship between these common elements in AD CT design and drug development.