Patient-Centric Clinical Trials Europe 2015

Jun 8, 2015 - Jun 9, 2015, London

Put the patient at the heart of the clinical trial

Partnership: The Game Changer in Alzheimer’s Research

A unique public-private partnership aims to change the face of Alzheimer’s dementia research by avoiding the duplication of research efforts. Danielle Barron speaks to those involved to find out why this new approach may finally lead to effective treatments for the condition.

Dr Serge Van der Geyten, EPAD Coordinator and Director of Neuroscience External Affairs, Janssen

Isolated research endeavors are becoming a thing of the past as the modern day global village allows close collaboration with international colleagues in the same scientific field.

One area that is set to benefit from such a collaboration is Alzheimer’s disease research. With the majority of drugs that entered the disease pipeline in recent years having failed, researchers in the area recognized a need for a synergistic approach that would permit expedited delivery of effective therapies.

Taking this concept of research collaboration to the next level is the European Prevention of Alzheimer’s Dementia (EPAD) Initiative.

Thirty-five partners from industry and academia have joined the European research initiative, with the goal of improving the chance of successfully preventing Alzheimer’s dementia and to better understand early aspects of Alzheimer’s disease before dementia develops. The European Innovative Medicines Initiative has allocated a not-insignificant sum of €64 million towards the project, which was launched late last year.

Avoiding duplication

Dr Serge Van der Geyten is EPAD Coordinator and Director of Neuroscience External Affairs at Janssen. He explains that the lack of headway in dementia research is partly due to overlapping research taking place in parallel.

“Everyone involved, not only pharmaceutical companies but also academic institutions, went their own way. And we went after our own targets, our own mechanisms and designed our own trials and, at times we were either duplicating efforts or doing something that was also being done in an identical way by another institution or pharmaceutical company. By the time those results were available, the other development programs were too far along to change gear,” he says.

One reason for the establishment of the EPAD public-private partnership was the promise of “learning from each other more quickly”, explains Van der Geyten. "We would avoid duplicating efforts by sharing data with each other.”

Emerging evidence

Professor Craig Ritchie is EPAD’s co-coordinator and also Professor of the Psychiatry of Ageing at the University of Edinburgh. He gives his view on why the Alzheimer’s research community had to finally take stock of what had been a decade and a half of largely fruitless research.

“If you think back 15 years ago, we were focused very much on the people who had dementia, who already had significant cognitive symptoms, functional impairment, problems connected to daily living and behavioral consequences of Alzheimer’s disease. In those populations, you saw the amyloid plaques and tau tangles as well as other pathologies. Predominantly, however, the pathology that really defined the illness was the amyloid plaque. So, (quite rightly) the focus of disease modifying therapies was on trying to reduce the formation of amyloid plaque.

“But now there is compelling evidence that in people who are in the earliest stage of cognitive symptoms, so called Mild Cognitive Impairment, there is often already substantial levels of brain amyloid. This creates a problem, because what you want to do is stop amyloid accumulating and if it is already well-developed in people with mild cognitive impairment then you have to intervene even earlier. One challenge is identifying people with low levels of amyloid in their brains who are likely to progress to dementia and then trial new medicines in that group”.

Identifying those people at high risk of the disease and who have no symptoms whatsoever, that’s the challenge that EPAD is going to address. In the care of people with cancer and other chronic conditions, if you can intervene early, you then have a better chance of affecting the course of illness".

Fundamental shift

Consistent trial failures and an evolving knowledge of the pathophysiology has demanded that research efforts are instead focused on people who do not have Alzheimer’s dementia– yet. This obviously begs the question of how to identify people on the cusp of developing Alzheimer’s dementia, and Prof Ritchie explains that it requires a shift in the fundamental way that people think about the condition.

“Identifying those people at high risk of the disease and who have no symptoms whatsoever, that’s the challenge that EPAD is going to address. In the care of people with cancer and other chronic conditions, if you can intervene early, you then have a better chance of affecting the course of illness. That’s why we have to draw the distinction between Alzheimer’s disease, which is the pathology, and Alzheimer’s dementia, which is the clinical syndrome that emerges as the pathology progresses.”

The right people

A core element of the initiative is the establishment of a European-wide register of 24,000 participants, and via characterization with biomarkers and cognitive measures, the 25 per cent with the highest risk of developing Alzheimer’s dementia will be selected for an observational study of approximately 6,000 subjects. It is estimated that 1,500 of those subjects will then become involved in the proof-of-concept studies.

“The big difference with how we are currently doing studies is that we will have characterized these subjects in a very detailed way, and we will have observational data on them for six months or a year and for some of them even longer by the time we start recruiting them in the proof of concept study. Because of this, the recruitment process should go more smoothly, as we know those patients who are willing to participate in a study, and we will have collected a wealth of data on them, so screen failures, which are quite high in current trials for Alzheimer’s disease, will be greatly reduced. So that part will speed up the execution of the trial.”

This novel approach involves designing studies in an adaptive fashion, he explains; adaptive design allows modifications to be made to the trial  while the study is ongoing.

“As we learn, we can change and adapt certain features of the trial. If we see that a particular treatment is more efficacious than another we could decide to increase the number of people that are randomized to that particular arm of the trial and if a treatment turns out to be not efficacious, we can reduce the number of subjects allocated to that arm of the trial,” says Van der Geyten, adding that this is markedly different to the traditional clinical trial model, which most of the time continues regardless of the efficacy data collected during the trial.

A win for patients

This means not only a faster path to drug development for the researchers, but also a significant benefit for trial participants.

“In the end, fewer patients will be exposed to a drug that is not efficacious and fewer patients will be exposed to placebo. The patients win,” he states.

In another first, patient organizations throughout Europe will be represented within the consortium by Alzheimer’s Europe.

“When we design our studies and discuss how to approach certain issues, the patients will have a voice,” adds Van der Geyten.

The EPAD umbrella

Many research consortia have sprung up globally as scientists and researchers accept the necessity of close collaboration – Ritchie currently leads the PREVENT study, a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer's disease. These current research projects will be continuing their work under the EPAD umbrella.

“Across the UK and elsewhere in Europe through EPAD, we will be able to draw those curves that indicate when the disease starts, how it progresses and how it relates to clinical features like memory loss. People in the PREVENT cohort and numerous other cohort studies across Europe will be the ones who are invited to join the EPAD cohort, and those may then be asked to join the actual clinical trial.”

The registry will be an ongoing source of information and will be an invaluable resource, added Ritchie.

“Models of Alzheimer’s disease will be developed, that can then provide individuals with their individualized risk of progressing. This ‘risk score’ will undoubtedly combine genetic, clinical and environmental risks with early evidence of disease as captured through biomarker abnormalities and very early/subtle clinical symptoms. In EPAD we will gather more and more data as the EPAD Cohort and Trial continues indefinitely, so we are continually learning about this pre-clinical disease population. We will analyze and re-analyze the data we gather, so we can continue to refine our models so we get better and better at predicting the probability any person has of their disease progressing towards dementia. With the trials we will do in EPAD, we concurrently can develop the treatments that will hopefully prevent this progression .”

Important breakthroughs

Dementia research is a particularly challenging field with a paucity of groundbreaking developments and where efforts are still at a very early stage in terms of elucidating the pathophysiology of the disease in order to exploit this for new targets.

Van der Geyten says this is now set to change for a couple of reasons namely the advent of new scientific approaches and technologies in clinical trials, such as the development of adaptive design, as well as various important breakthroughs in the understanding of the basic mechanisms involved in Alzheimer’s disease in the past five years.

“Bringing those together is what has accelerated this collaboration,” he admits.

Van der Geyten also explained that the group is not limiting themselves to the development of solely pharmacological therapies in the fight against Alzheimer’s.

“If down the line a partner wants to join, with perhaps a nutraceutical therapy, then they are also welcome. We are open to any new lines of research and therapy.”

Indeed, additional targets are now being explored with a renewed veracity, and these include mitochondrial dysfunction, cellular connectivity, and cytopathology. Where and when to hit these targets is now being teased out in the new wave of research.

“There is a long list of pathologies that might be important, and what we need to do within EPAD is work out how they are important, and when they are important, so that we can sensibly target the right part of the disease process at the right time in the right population,” explains Ritchie.

A game changer

Ritchie has called the EPAD initiative a “game changer” in terms of the way that Alzheimer’s therapies will now develop which target the earliest pre-clinical stages of disease.

“Every single element of the way we have done our trials in the past is being challenged and is likely to change. We are investigating earlier in the disease pathway, we are using adaptive trial design rather than traditional placebo-controlled trials, we are using an environment and trial centers that are partnered with the project rather than simply being paid a fee for services. We are looking at biomarker outcomes as well as clinical outcomes. We have really thrown the whole thing up in the air and challenge every design and delivery element of clinical trials for Alzheimer’s disease” he states emphatically.

The greatest chance

I would hope, with some degree of confidence, that we will we have a new drug for Alzheimer’s disease in the clinics in the next 10 years".

Ritchie believes that the initiative will produce effective therapies for the condition sooner rather than later.

“If we can change the way we do drug development, then I think this will give ourselves the greatest chance of being able to develop drugs to prevent Alzheimer’s dementia. We may have the drugs already but now we have got the right framework in which to examine if they work. I would hope, with some degree of confidence, that we will we have a new drug for Alzheimer’s disease in the clinics in the next 10 years.”

Is it the case that pharmaceutical companies are finally willing to collaborate as they bemoan the many millions of dollars that has already been spent in the field of dementia research with very little return to show for it?

Van der Geyten disagrees, saying the reverse is true.

“What pharmaceutical companies want is a solution for Alzheimer’s disease, faster than we would be able to do as individual companies. A consequence of this collaborative approach is of course that if we do everything more efficiently and faster, then we are going to end up with a quicker return on investment. But that’s not the driver – the driver is that we have been trying to develop products for Alzheimer’s disease for 15 or 20 years. The last drug for Alzheimer’s disease was memantine and that was approved more than 10 years ago.”

He admits that one of the main advantages for industry, however, is ‘de-risking’ the final step in clinical development.

“We are removing the risk from the switch from phase II proof of concept studies to phase III so that we don’t have those major failures we have experienced in recent years. The big outcome from this will be de-risking the confirmatory phase of drug development.”

Sharing a common aim

According to Ritchie, the synergy of academia and industry makes the collaboration a no-brainer.

“It is absolutely critical we don’t draw too big a distinction as to whether we are contributing to this initiative from an academic or commercial perspective  – we bring different strengths to the table. It is not one leading the other. EPAD is a massive synergy of the strengths of the academic world and the commercial world. We share a common aim and that is to help prevent Alzheimer’s dementia. The less we see that distinction, the more successful we will be.”

Ritchie admits that although he has worked with industry partners for many years, EPAD is the “most equal” partnership he has experienced.

“This has to be the way forward. For these significant, major, global challenges that we face in healthcare, we have to work together in significant, major, global projects. The model of smaller pockets of people and groups across the world doing similar research as each other but in relative isolation just isn’t going to work to deliver the breakthroughs as quickly or effectively as people at risk of dementia demand and deserve.

“Major challenges need substantial funding and global collaboration.”

Patient-Centric Clinical Trials Europe 2015

Jun 8, 2015 - Jun 9, 2015, London

Put the patient at the heart of the clinical trial