Abstract
The devastating impact of Alzheimer’s disease (AD) spares no one. Given the economic and societal consequences, research and development for AD is presently witnessing a ‘call to action,’ yet the unmet needs of patients and caregivers are enormous. Moreover, despite the scientific advances and growing interest in public-private partnerships (PPPs), there are insufficient funds to support current and future PPP initiatives that aim to benefit all stakeholders. This article highlights a journey based on my own professional experiences as a neuroscientist, drug developer, and family member of a loved one suffering from AD. From my perspective, we must share our expertise as scientists and caregivers, our clinical trial data, our drug development tools, and our discoveries – just as we all share the burdens of this dehumanizing disease.
Innovation in scientific advances and developments for Alzheimer’s disease (AD) is accelerating the pace and sense of hope for patients and families. Exciting developments in molecular imaging agents, novel genetic discoveries and innovative technology developments are paving the way to identifying new ways to diagnose and treat patients with a vision for personalized medicines in the future. Yet the challenges for drug development for AD are daunting.
The numerous late-stage failed clinical trials, each of which on their own is a disappointment, when combined collectively during the past several years, leads to a sense of growing concern as to what viable options are going to prove successful for the future. Challenges for AD and chronic neurodegenerative diseases, relative to other disease conditions, include long duration treatment required, insensitive end points and clinical measurements, patient heterogeneity, lack of sensitive biomarkers that track with clinical outcome, requirement for drugs to cross the blood–brain barrier, animal models that do not recapitulate human disease and single-target hypotheses/monotherapy strategies. There is also increasing recognition of the importance of pursuing targets beyond amyloid-based therapeutics Citation[1] and some concern that the pursuit of a single hypothesis may impede future success Citation[2,3]. Learnings from recent large negative Phase III trials also indicate that a significant number of subjects are recruited into trials that are unlikely to have AD pathology Citation[4].
Early days in developing AD drugs
During my over 30-year experience as a neuroscientist, most of which was in large pharmaceutical companies, I had the honor of collaborating with numerous outstanding scientists. In the current climate, I find it enlightening to look back 25 years ago to the era where I initiated my focus on AD drug development. By focusing on animal models and target validation, I contributed to numerous scientific discoveries at a time when the amyloid hypothesis was at its infancy. From 1990 to 1995, the team I worked with included pioneers of amyloid discoveries at Eli Lilly, Athena Neurosciences (Elan) and academia (Dr. Dennis Selkoe). The team was feverishly transfecting novel genes associated with familial AD into cells and developing and implementing high-throughput screens to identify novel amyloid-reducing candidate drugs. The screens were being run prior to the discoveries of β-secretase-1 and γ secretase. I took part in in vivo model characterization to examine the phenotype of novel genetic mouse models; in parallel, we were injecting amyloid purified from human AD brain and/or synthetic amyloid into the brains of mice, rats, guinea pigs and nonhuman primates Citation[5] in hopes of demonstrating in vivo neurotoxic properties of amyloid as reported in the literature. It was an exciting time to be developing drugs for AD. There was huge enthusiasm for the science as well as an infectious optimism that a disease-modifying therapy was on the horizon. Teams were inspired and invigorated to partner and collaborate for the benefit of the field as a whole. I felt at this time that I was part of the leading edge of discovering the first ever disease-modifying treatment for AD.
Fast forward to 2013
As a scientist at the bench on the brink of such seminal discoveries, I would be shocked to fast forward 25 years, a time when dozens of amyloid-lowering agents have been administered in clinical trials to thousands of patients with the awareness that there is still no approved disease-modifying treatment. I would also be devastated to think that I would be witnessing the impact of AD on my own family; in 2008, my own mother was diagnosed with AD. Nothing prepared me for the challenges our family continues to experience. Gaps that patients and families face, such as stress, financial strife and pain of seeing loved ones suffer, all contributed for me to a personal sense of defeat and inability to help, despite a successful professional career partnering with leading experts in the world, none of whom could help.
What’s holding up progress?
During the intervening years of my career, I served as a bench scientist followed by scientific leader/lab director at three large pharmaceutical companies. I focused my research on target identification and validation for several different nervous system disorders. Having evaluated thousands of therapeutic compounds in diverse animal models and cellular model systems, none of the compounds made it successfully into humans as a marketed drug. I personally witnessed the impact of three different mergers, multiple relocations, new leadership, changing cultures and corporate changing business models on the efficiency of drug development. With each career transition, it became more difficult to endure the duplication of effort from what was being done at the previous company. Every time a drug candidate failed in the clinic, it became more and more difficult for me to mobilize energy and optimism for the next therapeutic target in the pipeline. When a drug fails, it is nearly impossible to garner resources to continue working on the target, understanding why it failed and applying those learnings to the next drug target in the pipeline. The amount of resources lost when a drug fails is not apparent, and new resources become completely dedicated to the next target. It was clear that industry stood facing the task of advancing the next candidate without understanding why the previous drug failed.
Joining forces to make a difference
After learning that my mother had AD and then 2 years later that my brother was diagnosed with young onset Parkinson’s disease (PD), I realized I could not endure the frustration of yet another failed therapeutic trial. My own passion for making a difference drove me to explore different career options. In 2011, I had the honor of joining the Critical Path institute (C-Path), a nonprofit public–private partnership (PPP) formed to deliver on the vision of FDA's Critical Path Initiative. C-Path orchestrates the sharing of data, expertise and knowledge among industry, regulatory authorities, government, patient advocacy groups and academia in the precompetitive space to generate the evidence needed to improve the drug development pathway. As the executive director of the Coalition Against Major Diseases (CAMD), I lead a team of diverse experts in a precompetitive consortium dedicated to accelerating treatments for AD and PD.
How CAMD accelerates drug development
CAMD has successfully facilitated collaborative efforts to develop tools aimed at expediting drug development and maximizing the potential for success in future drug trials Citation[6–8]. Already, these efforts have led to the submission and acceptance of a qualification opinion by the EMA on the use of hippocampal volume as a biomarker for enriching predementia clinical trials with appropriate subjects Citation[9], the establishment of a database incorporating placebo data from 6500 subjects, the development of the first AD CDISC clinical trial data standard that will facilitate data sharing and the first ever regulatory endorsement of a clinical trial simulation tool for AD. CAMD aligns efforts with other PPPs so as to create synergies and avoid duplication of effort. I am personally grateful to have the opportunity to lead such an impactful initiative, yet still feel a sense of hopelessness in not being able to do more to improve the daily lives of my own family members. I have gained tremendous respect for patient advocacy groups, a group of stakeholders who truly are at the frontlines in passionately driving awareness for increased funding to help all those suffering with this disease. There is a desperate need to address the vast number of unmet needs for those suffering from the burden of this disease.
Expert commentary
With the growing awareness that no one single entity or organization is able to solve the challenges in developing effective treatments, the number of PPPs dedicated to AD has escalated Citation[10]. There is a desperate need for increased funding of PPPs as well as alignment and coordination among these efforts.
Five-year view: a speculative viewpoint on how the field will evolve in five years’ time
In 5 years, it is anticipated that the explosion in data sharing, big data and innovative technologies will positively impact AD drug development and transform approaches to healthcare. Increased participation of patients and caregivers in drug development, different business models and growing investments in PPPs, will improve the sense of global commitment and alignment of efforts. There is an urgent need for approval of new effective treatments to support continued investments by diverse stakeholders and a global need for aligning of efforts. With this call to action, it is my sincere hope that 25 years from now, my own children do not have to face the helplessness that this disease brings to all.
Key issues
Alzheimer’s disease (AD) economic, emotional and societal burden is unsustainable.
Scientific discoveries have not advanced at a pace to parallel the growing unmet needs of families and patients suffering from AD.
There is an increased need for precompetitive collaboration and alignment across them.
There is a significant requirement for funding of public–private partnerships (existing and new ones).
It is absolutely essential to learn from the past by data sharing, consensus science and positively influencing the regulatory landscape.
There is a critical need to engage patients, family members and advocacy organizations.
Acknowledgements
I would like to thank Dr. Lynn Hudson, executive director of the Multiple Sclerosis Outcomes Assessment Consortium and chief scientific officer at C-Path, for review of this manuscript. I dedicate this review to my family and to those heroic caregivers who, with limited salaries, dedicate their days and nights to caring for the needs of my mother and all those like her suffering from AD.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
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