Clinical Research: Phase 1 - Phase 4

A Vast Unmet Need: Challenges In Alzheimer’s Clinical Trials

Dementia is a growing global epidemic, affecting nearly 47 million people worldwide. That number is expected to approach 75 million by 2030, when the cost of patient care is forecast to reach $2 trillion. And the trend will only accelerate: By 2050, it’s estimated that 115 million will suffer from some form of dementia. Alzheimer’s disease is by far the most common of these afflictions occurring late in life, making it imperative that we develop new pharmacologic therapies.

More than three decades ago, the cholinergic hypothesis proposed that degeneration of cholinergic neurons in the basal forebrain — and the associated loss of cholinergic neurotransmission in the cerebral cortex, hippocampus, and other areas — contributed significantly to cognitive deterioration in Alzheimer’s disease. That hypothesis led to development and FDA approval of the first Alzheimer’s drug, tacrine, in 1993.

Despite clinical trials of numerous agents over a wide range of mechanisms that include neurotransmitter modulation and disease-modifying therapy targeting amyloid and tau, the last new Alzheimer’s medication, memantine, was approved in 2003. The only path to regulatory approval for treatments is well-conducted clinical trials, and trial failures may result from inadequate understanding of mechanisms of action and/or poor target engagement, inadequate study design, the stage of the disease along the continuum studied, inclusion of participants without Alzheimer’s pathology in clinical trials, and limited power of endpoint measures.

There are currently 23 drugs in Phase II and III trials targeting amyloid protein buildup in the brain, while 28 drugs are targeting neurotransmitter activity. Twenty-seven Alzheimer’s drugs in Phase III clinical trials and eight drugs in Phase II trials may launch in the next five years, according to the Alzheimer’s pipeline analysis presented at the Alzheimer’s Association International Conference in July 2017. Preventing or delaying disease onset, slowing progression, and improving the symptoms of this disorder are critically important.

Of 143 currently active Alzheimer’s trials, 71 percent are being conducted in the United States. While the U.S. has more trial sites than any other single country, the majority of sites are in other countries. Recruitment and site activation processes for Alzheimer’s clinical trials face a number of challenges, and consequently, 85 to 90 percent of U.S. trials experience delayed recruitment. The increasingly global nature of these trials emphasizes the importance of considering the ethnic and regional factors that may influence the outcome.

Many Alzheimer’s trials rely on subjective endpoints as the primary measures of efficacy. Clinicians and trial sites vary widely in their experience administering assessment instruments, leading to unintentional variability of data. To overcome this challenge, many sponsors and CROs implement thorough training programs targeted to all raters and robust and ongoing rater monitoring and quality assurance programs. In addition, clinical assessments using scales to measure cognitive impairment, disability, quality of life, or global disease severity are affected by symptomatic effects of therapies and, in the short term, cannot differentiate this effect from disease modification. An alternative approach could be using surrogate outcome biomarkers that objectively measure characteristics of the disease. Unfortunately, there is no single accepted surrogate outcome biomarker for Alzheimer’s disease.

Alzheimer’s drug development is costly, time-consuming, and inefficient. Site functions, trial design, and patient recruitment all require improvement. At 99.6 percent, the trial failure rate is the highest of any therapeutic area. Innovation is critical to shortening the development cycle of new therapies and identifying drugs that have limited or no therapeutic potential.

This webinar will review the current global pipeline of Alzheimer’s trials and their geographic locations, describe innovations in trial design, and promote consideration of optimal clinical trial processes, including preclinical patient populations, clinical assessments sensitive to the earliest disease-related changes, and biomarkers as outcomes of clinical trials.