11 Aug 2016

Part 1 of a three-part story.

The biggest story at the Alzheimer’s Association International Conference, held July 22-28 in Toronto, unfolded rather quietly. It took place in off-site or pre-meetings, and in a sparsely attended session on the last morning, when a majority of conventioneers had left. It is the story of how multiple powerful interests on either side of the Atlantic and Pacific oceans have coalesced to try to fundamentally reorganize the way clinical trials will be done on Alzheimer’s disease starting in the near future.

Here is the vision: Rather than neurologists waiting for symptomatic patients to come through their doors, and perhaps suggesting a trial after delivering a diagnosis, the new modus operandi for recruitment will be one of massive efforts to tap into aging but outwardly healthy segments of societies. In other words, the new initiatives are about locating people who do not know they are heading toward Alzheimer’s dementia, and who had no plans to show up at a memory clinic anytime soon. “This really changes how the sites do business. It becomes a game of outreach. It is very exciting,” said Stephen Salloway of Butler Hospital at Brown University, Providence, Rhode Island.

Drug companies and academic leaders, egged on by advocates and funders, are setting in motion this reorganization of Alzheimer’s clinical research. “We are at an inflection point in terms of how people are coming together. It really is true that academics, pharma, and even individual governments are realizing they cannot do it alone. The barrier toward collaborating and sharing and adopting standardization, and enabling the larger initiatives, is coming down in pharma,” said Luc Truyen of Janssen Research & Development, a company of Johnson & Johnson.

George Vradenburg, who leads the Global Alzheimer’s Platform (GAP), views it like this: “The Alzheimer’s field has been thinking too small. We need to link up patient registries, health plans, large physician groups, and trial sites to solve the fundamental challenge of getting participants into prevention trials.” Academic leaders agree. “This is about creating and executing a whole new paradigm for how to do trials for AD,” said José Luis Molinuevo of Barcelonaβeta Brain Research Center in Barcelona, Spain, who co-leads the European Prevention of Alzheimer’s Dementia (EPAD). Industry is actively on board. “We have to change how we evaluate our compounds,” said Truyen. He previously co-led the development of galantamine and bapineuzumab; his job nowadays is to oversee Janssen’s role in EPAD, GAP, and related efforts in the United Kingdom. In essence, the pharma industry’s support for these joint initiatives reflects an acknowledgement, expressed in 2014 by Sanofi executive and former National Institutes of Health director Elias Zerhouni that “pharma has to stop playing solo.” 

What are GAP and EPAD? Centered in the United States and Europe, respectively, they are the two largest and most advanced AD trial reform initiatives, though similar efforts are coming along in Canada, Australia, and Japan, as well. GAP grew out of USAgainstAD and the Global CEO Initiative, patient advocacy and industry groups, respectively, that were founded by Vradenburg and have since come to exist under the umbrella of the GAP Foundation, a 501c3 organization. The foundation aims to revamp the trials system so it can evaluate more candidate drugs faster, less expensively, and with a greater chance for success. It has secured commitments for $23.2 million from nine companies and several foundations thus far, and on July 1 resubmitted a large National Institute on Aging grant. For its part, EPAD is a project of the Innovative Medicines Initiative (IMI), the public-private partnership funded jointly by the European Commission and the continent’s pharmaceutical industry association, EFPIA. In January 2015, EPAD received a five-year grant of €64 million. 

Both projects engage leaders from all sectors of AD research in Europe and North America. GAP has attracted academic trial specialists such as Jeffrey Cummings, Reisa Sperling, Paul Aisen, Salloway, and Rachelle Doody, industry scientists including Andy Satlin, Steve Paul, Richard Mohs, Russ Barton, and Truyen, as well as business leaders; it partners with some 40 companies, academic sites, and philanthropy groups. EPAD is organized into eight topical teams called “work packages” that engage leaders throughout the AD research community in Europe. EPAD’s academic leaders include Simon Lovestone, Craig Ritchie, and Molinuevo; its industry leads include Truyen and Satlin, and it partners with an equally large, and overlapping, set of academic and pharma groups as GAP.

Why attack the problem of AD therapy research at the systems level? Essentially, GAP and EPAD leaders cite the law of holes, that is, “If you find yourself in a hole, stop digging.” In 2013, companies and academics alike were reeling from a string of late-stage trial failures, and when bapineuzumab went under in Phase 3 as well, they did decide to stop digging. They stepped back to acknowledge that AD pathology was present in the brain earlier than they had thought. They asked themselves how they were going to find these early stage patients to test their disease-modifying therapies. They decided to act because their drug portfolios were broadening, and they needed a better way to study those medicines.

“It used to be ‘fire and forget.’ Industry would start huge Phase 3 programs without taking the time to learn if was going the right way, and we’d end up four years later with a negative study,” Truyen told Alzforum. Richard Mohs agreed. “When a trial ends, its infrastructure goes away, and staff leave the sites. There is no system,” said Mohs, who since retiring from Eli Lilly splits his time between the biotech startup AgeneBio and GAP. The field was ready to put something into place that allowed researchers to learn faster. Conversations in 2013 led to a consensus that to gain access to the right patients, and test more drugs in them efficiently, a standing, integrated, continuously active trials platform would be built, and new methodology and trial designs implemented. The result in Europe was the IMI EPAD grant in December 2014, in the United States it was GAP’s launch in 2014. 

EPAD and GAP have three main components in common, though they use different terms.

1. They are exploring ways to access large numbers of participants who are well-characterized and enter a longitudinal cohort study. Both EPAD and GAP are intending to funnel at-risk people into deeply phenotyped biomarker cohorts, and from there into therapy trials.

2. They are certifying networks of sites that use streamlined procedures with a standing staff. EPAD is bringing online 30 so-called trial delivery centers; GAP is expanding a pilot “GAP Net” of 11 sites by adding 20 this year and another 30 in 2017.

3. They will innovate by testing adaptive trial designs. On this goal they differ in more than terminology. EPAD intends to run Bayesian adaptive, Phase 2 trials in pre-dementia populations. The trials will feature interim analyses every three months to evaluate whether the intervention at hand slows cognitive decline. Different EPAD trials will adapt on different intermediate phenotypes specific to the intervention, for example lowering Aβ for an anti-amyloid drug or lowering tau for a tau-based drug. EPAD considers the first Bayesian Phase 2 proof-of-concept trial of BAN2401 a potential model (Satlin et al., 2016). A drug will “graduate” from an EPAD trial if it meets a predefined cognitive outcome, and the company would then take it through confirmatory Phase 3 trials and regulatory approval on its own. In contrast, GAP intends to run both Phase 2 and Phase 3 trials of preclinical, prodromal, and dementia stages of AD, using drugs aimed at the disease’s cognitive and behavioral symptoms. GAP trials will start off with parallel group designs. Both EPAD and GAP hope to start their first trials in late 2017.

Flow chart of the standing trials platform being built by the European Prevention of Alzheimer’s Dementia project. [Courtesy of EPAD.]

At AAIC this summer, discussions focused on progress on points 1 and 2, as does this news series. For more on how EPAD and GAP are trying to find trial participants, see Part 2 of this story. For the latest on how site networks are forming, see Part 3.—Gabrielle Strobel

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References

Therapeutics Citations

1. Galantamine
2. Bapineuzumab

News Citations

1. Access: How to Bring People in ‘From the Wild’? 11 Aug 2016
2. Playing Where the Puck Is Going to Be: Trial Sites Skate Toward GAP Net, EPAD TDCs 12 Aug 2016

Paper Citations

1. Satlin A, Wang J, Logovinsky V, Berry S, Swanson C, Dhadda S, Berry DA. Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease. Alzheimers Dement (N Y). 2016 Jan;2(1):1-12. Epub 2016 Feb 4 PubMed.

External Citations

1. pharma has to stop playing solo
2. GAP Foundation
3. EPAD

Further Reading

No Available Further Reading