In the race for new therapeutic drugs, many contenders fall to the wayside as they shuttle through the clinical trials pipeline. Rigorous testing often sees increasing failure rates as drugs pass from phase I studies into safety to phase II studies for efficacy, and ultimately phase III studies tasked with assessing a barrage of factors in a larger group of subjects. Whilst these daunting odds are expected, in a recent study in Alzheimer’s Research & Therapy by Jeffrey Cummings from the Cleveland Clinic Lou Ruvo Center for Brain Health, USA, and colleagues, the development of therapeutic drugs for Alzheimer’s disease is shown to be particularly subject to failure. Accessing a decade of trial data from the US National Institutes of Health database, ClinicalTrials.gov, the rate of attrition of drugs in the development pipeline was quantified. Here Cummings explains why there aren’t enough clinical trials for Alzheimer’s disease therapeutics, how this can be addressed, and the implications of their results.
Why did you choose to use ClinicalTrials.gov data to record the trends in Alzheimer’s disease drug development?
This is the most comprehensive database on clinical trials and has been mandated since 2007. It had not been analysed for Alzheimer drugs. There have been several high profile recent failures in drug development – bapineuzumab, semagecestat – but no detailed evidence-based analyses of the Alzheimer’s disease drug pipeline. We wanted to get an overview of the process and studying the decade 2002-2012 plus an analysis of the current pipeline gave us a comprehensive view of how compounds move through the pipeline, what targets are being addressed, and what the success and failure rates are.
Why are there relatively few clinical trials for Alzheimer’s disease therapeutics, considering the magnitude of the problem?
There are many contributing factors to the low number of trials. The investment of the US National Institutes of Health (NIH) in Alzheimer’s disease is relatively modest – $650 million compared to $6 billion in cancer, for example – so the rate of target identification is low. Similarly, many drugs are first discovered in academic laboratories and then out-licensed to biotechnology and pharmaceutical companies; the low rate of investment in discovery leads to few candidates to assess. At the biotechnology and pharmaceutical level, the high failure rate, long trials required, and high cost discourages investment in this area. Venture capital is less available in this area because of the high failure rates. Many biopharma groups have exited central nervous system drug development.
How can this situation be improved?
Funding is need to advance Alzheimer’s disease drug development; this is true at every level of the drug development ecosystem. More NIH funds are needed for Alzheimer’s disease research including target identification and candidate therapy generation. Novel mechanisms for bringing in more venture capital are required. Public-private collaborations and support from philanthropy and advocacy groups are another means of supporting drug development. Legislation that extends patent protection, incentives for working in chronic disease and the US Food and Drug Administration fast-track channels are also among the things to be done.
What are the implications of your data for future Alzheimer’s disease research and funding?
The analysis shows that Alzheimer drug development is in a disastrous state and much more must be done to the respond to the looming epidemic. Around 10,000 baby boomers turn 65 every day and enter their Alzheimer’s disease risk years. Against this tsunami of therapeutic demand we have a trickle of drug development. Our current efforts are vastly incommensurate with the need. We hope our study will show the situation so dramatically that public concern will be amplified and more funds will be found.
What role do the Open Access and Open Data movements have to play in aiding progress in Alzheimer’s disease research?
The widespread availability of data is critical to advancing the Alzheimer research agenda. Scientists sharing information is critical to advancing drug discovery and development and the free flow of information is the highway down which scientific progress will drive.
One of the outcomes of the G8 dementia summit, held in London, UK, in 2013, was to identify a cure, or disease-modifying therapy, for dementia by 2025. How achievable do you think this is?
Discovering a cure seems unlikely but I think it is possible that we will have identified a disease-modifying drug by then. The time frame of 2025 is very tight given how long it takes to develop drugs – 13 years on average for Alzheimer’s disease drugs to make it from the laboratory to the end of a Phase III clinical trial – so any adjustments we make now will not come to fruition for a decade. If we do not increase our efforts now we will not have new therapies by 2025.
Alzheimer's Research & Therapy 2014, 6:37
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