Alzheimer’s Sessions at DIA 2013 focus on Challenges, Innovative Approaches in Drug Development

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By the year 2050, 115 million people will be living with dementia, worldwide, according to the World Alzheimer’s Report. Currently, 36 million people have been diagnosed with the condition, and its global impact is growing every year.

Three sessions during the DIA 2013 49th Annual Meeting in Boston focused on Advancing Alzheimer’s innovation. The first session focused on the global impact of the disease and key strategies that governments, advocacy groups, and industry are taking to elevate Alzheimer’s on the global agenda.

George Vradenburg, co-founder and chairman of US Against Alzheimers, argued for intervention by the G8 countries, as was done more than a decade ago to change the tide in treatment for the HIV/AIDS epidemic. After the G8 pledged $1.3 billion to the Global Fund to Fight HIV/AIDS, Tuberculosis, and Malaria, a turning point was reached in reducing the devastation of those disease, worldwide.

In May 2013, British Prime Minister David Cameron announced that the G8 would take the lead in addressing Alzheimer’s on a global level. Vradenburg belives that Mr. Cameron’s declaration may prove to be a turning point for Alzheimer’s as one of this century’s greatest social, health, and economic challenges.

Vradenburg argues that the G8 must require stakeholders to increase the scope of research resources and increase the volume and velocity of new treatments to those at risk for Alzheimer’s. Current costs of developing therapies are too high, timelines are too long, and risks are too great. According to Vradenburg, the G8 can solve this problem by leading the effort to create a global financing mechanism for Alzheimer’s research and championing the regulatory harmonization and global clinical trials infrastructure needed to speed drug testing and approvals and enable development teams to reduce drug evaluation uncertainty.

Also during the first session, Dr. Reisa Sperling, of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, Massachusetts General Hospital, and Harvard Medical School, discussed the possibility and opportunity of detecting and treating Alzheimer’s a decade before dementia begins. Converging evidence from genetic at-risk, biomarker, and imaging studies show that the pathophysiological process of Alzheimer’s begins many years prior to the diagnosis of dementia. Animal studies, and recent clinical trials also suggest that earlier intervention than is currently being used is required to properly treat the disease. Similar to other diseases, such as cancer and heart disease, the best opportunity to intervene in Alzheimer’s is likely before clinically evident symptoms are present. Delaying the onset of dementia by just 5 years could save millions of dollars in Medicare costs alone.

Rudolph E. Tanzi, Ph.D., the Jos. P and Rose F. Kennedy Professor of Neurology at Harvard Medical School and at Massachusetts General Hospital, lent support to the idea that Alzheimer’s can and should be attacked and treated earlier. In recent years, researchers have discovered a strong genetic component related to contracting the disease as well as indications regarding gender, metabolic disease, and brain injury that also point toward eventual Alzheimer’s development. Tanzi’s encouragement is for early prediction, which leads to early detection, which ultimately leads to early prevention of the disease.

What is known about the path of Alzheimer’s deepened in the last decade or two from understanding brain pathology, including amyloid plaques, tangles, and inflammation, which are all related to Alzheimer’s, and expanding that into a look at four genes (APP, PSEN1, PSEN2, APOE). Defects in these genes, along with increased accumulation of A-beta, seem to point toward eventual Alzheimer’s as well. Excess A-beta leads to tangles and neurodegeneration, and as tangles spread from neuron to neuron, the disease develops further. Thus, early detection and treatment of these tangles becomes urgent.

Tanzi pointed to a March 2012 article in Time Magazine in which Dr. Francis Collins, director of the National Institutes of Health, discussed the highest priorities for Alzheimer’s research. They included the “application of comprehensive DNA sequencing to identify additional gene variants that play a role in the various forms of the disease; then the development of new cell-based models of Alzheimer’s disease; and third, the testing of new therapies in people at high risk for Alzheimer’s disease.”

The second session focused on caregiver support and patient advocacy measures in Alzheimer’s. A small number of nations — France, the United Kingdom and Australia among them — have created comprehensive national policies to manage Alzheimer’s disease and to offer compassionate care to its sufferers. The private sector is also starting to respond to the growing need to help support patients and caregivers, whether in institutions or at home.

With PDUFA V and MDUFA III patient-focused drug development initiatives from the FDA, there is increased interest in garnering real-world evidence and working on patient-reported outcomes, especially for early dementia. The idea is to embrace correlation rather than cause of the disease, and using “big data,” increase data collaboration and improve the ability to manage data at all stages of the disease. The way to do this is to cultivate relationships among payers, regulators, and patients, with well-stated rules of engagement.

Another positive step forward in this area is the Global CEO Initiative on Alzheimer’s Disease (CEOi). The public-private partnership was initiated by leading global corporations and involves nonprofit and governmental organizations to identify and advance high-priority activities necessary to prevent and treat Alzheimer’s disease by 2025. The CEOi aims to spur innovations that will improve the diagnosis, prevention, treatment, and care for Alzheimer’s by improving the productivity of R&D investments and reducing the time, costs, and regulatory risks. Other goals of the initiative include facilitating the development of new models for care and care delivery.

The third, and final, session focused on challenges and innovative approaches to clinical trial design and drug development for Alzheimer’s. Only about 8% of new drugs that enter clinical trials to treat the central nervous system (including Alzheimer’s disease), make it to the US market. The rate of failure for Alzheimer’s drugs that make it to phase 3 development is even more troubling.

During this session, Dr. Andrew Satlin, executive vice-president of Eisai, Inc., shared his research on the Bayesian adaptive trial design approach to phase 2 clinical trials. The approach was developed due to the need for proof-of-concept before phase 3 trials begin. With the inherent challenges of studies shifting to earlier disease, and slow progression of long trials with large sample sizes come multiple uncertainties, such as dose and regimen, treatment effect size, and sample size. But the Bayesian adaptive design allowed for informed and efficient decision making through ongoing analysis of existing study data, and therefore, the opportunity to make important decisions earlier in the clinical trial process.

The Bayesian method is a novel approach that uses interim analyses to update randomization allocation and assess futility or success, thus mitigating risks associated with larger and longer trials. It allows for early termination if the drug is ineffective and early advancement to successful phase 3 trials and better dose selection.

Esai used this model in its phase 2 trial of the investigational agent BAN2401, a monoclonal antibody directed at amyloid protofibrils/oligomers. The company plans to use a similar approach for phase 2 with a BACE1 inhibitor.

Dr. Sperling returned during this session to discuss challenges and possible ways forward in phase 3 trial design for Alzheimer’s. With multiple failures pointing to questions of biomarkers usefulness in Alzheimer’s trials, Sperling advocated for a new approach, and discussed the Anti-Amyloid Treatment in Asymptomatic AD (A4) trial as a good example of this approach.

The goal is to be able to select individuals most likely to decline based on neurodegenerative markers or evidence of cognitive impairment or decline. If we can catch people on the tipping point of decline, early enough to save them from dementia, but late enough that they have some symptoms that can be improved, it would be ideal. The key is to find a “critical window” and develop more sensitive measures to track the earliest changes in cognitive function.

Download your free copy of Spotlight On…Alzheimer’s Disease today for insight into the key market players and deal highlights for this therapy area.

Download Beth Nuskey’s conference report from DIA 2013, Pharmaceutical Research Analyst for Thomson Reuters here.

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