On 26 January 2010, at an ordinary airport hotel in Phoenix, Arizona, an extraordinary gathering unfolded. High-level representatives of 19 different pharma, biotech, and medical companies from across the U.S. and Europe—businesses that compete fiercely for the same market—spent the entire day cooped up in one room. There they engaged in a searching, at times surprisingly candid, discussion with academic research leaders, funders, and regulatory and statistics experts. Their topic? How they could set aside their competition in order to advance a shared vision of testing candidate drugs in people who are at imminent risk for Alzheimer disease but have no symptoms. In other words, these are future patients who, pathologically speaking, may already have Alzheimer’s but as yet without the dementia that epitomizes the disease in most people’s minds.

Alzheimer’s prevention has become a favorite buzzword of late, but approaching this goal with clinical trials of candidate AD drugs is difficult to do. This meeting represented perhaps the most advanced effort to date to actually pull it off. Called the Alzheimer’s Prevention Initiative (API), the effort is the brainchild of Eric Reiman and Pierre Tariot at the Banner Alzheimer’s Institute and the Arizona Alzheimer’s Consortium in Phoenix, Arizona. They and their Banner colleagues had invited the group of 50 people to this meeting. Riding the collaborative wave created by previous shared efforts such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Alzheimer's Disease Cooperative Study (ADCS), and the Dominantly Inherited Alzheimer Network (DIAN), these scientists are trying to build a coalition of academic and industry leaders with other stakeholders to begin, already in 2011, biomarker-driven drug trials initially in two separate sets of people who, based on their genetic status and age, are at the highest imminent risk of symptomatic AD. One group are middle-aged adult relatives of a large extended family near Medellin, Colombia, who are stricken with a deterministic early onset presenilin 1 mutation. The other group are people in their sixties and seventies in the U.S., and potentially abroad, who carry two copies of the ApoE4 gene. The API has joined forces with DIAN, the international network for families with dominantly inherited (i.e., APP- and PS-mutant) AD, which is already enrolling for an observational study and has begun planning its own drug study to offer to DIAN participants in the next year or two, as well.

“My dream is to get parallel preclinical trials going in these high-risk people and also the general population. We want to launch an era of prevention research where the field at large evaluates pre-symptomatic treatments rigorously and rapidly in randomized clinical trials,” said Reiman. If this seems ambitious, that’s because it is. Talking about the benefits of prevention of AD is stating the obvious, but the day’s discussions highlighted the fact that many hurdles remain. They also made clear that pharma’s pre-competitive spirit comes to a cold stop when the discussion broaches their own or their competitors’ drugs (see Part 4 of this series). Even so, most attendees urged Reiman and Tariot to press on with their proposal and indicated that they would want to be part of it.

That’s in part because concern is growing in academia and industry that the conventional mode of testing drug candidates in people with mild to moderate AD using parallel-arm study designs may not produce impressively effective therapies any time soon. There is a palpable concern that this conventional treatment trial design could sink the prospects of what might have been a respectable pre-symptomatic therapy before a way is found to test for the latter. A new model is needed, and in Phoenix, leading scientists of all backgrounds voiced remarkable consensus that the time is right to break out of the mold. Moreover, it appeared the company scientists, who work within the strategic and legal constraints of big pharma, mostly removed from patients, welcomed initiatives from physician-researchers who personally take care of people they know will get AD fairly soon and who are chomping at the bit to try to stave off that day. “In our blood-and-guts, clinical, day-to-day environment, we come under a lot of pressure to act boldly. That is a good thing,” said Tariot.

To the general public and to many doctors, Alzheimer disease is largely synonymous with dementia and the progressive loss of self and independence. Typically, people develop symptoms, seek a diagnosis, and then take drugs. However, since the advent of biomarker and imaging research as far back as the early 1990s, scientists have gradually been parsing what it means to have AD with greater nuance. They have observed the disease’s molecular changes start to take place many years before people realize anything might be amiss in their brains. With this, the notion of a pre-symptomatic, biologically defined decade or so began to take shape. By this notion, the period of overt suffering most people equate with having AD would constitute merely the denouement of a much longer disease process. As is the case in other medical conditions, the end stage of organ failure of a disease process may be hardest to treat, raising hopes for a wave of drug trials in this newly defined, clinically “silent” phase. An oft-quoted analogy is heart disease, where preventing atherosclerosis is more successful than treating heart failure. It also requires different drugs. The deeper implication here is that some of the investigational drugs currently tested for treatment might do better in prevention, and that a whole separate set of drugs will be needed for treatment.

Scientifically speaking, the first trials proposed by API would represent pre-symptomatic treatment, giving study medication to people who are cognitively normal. It would be called secondary prevention if there is evidence of the brain changes that signal predisposition to clinical AD. Scientists use various terms and definitions to best describe the disease stage prior to mild cognitive impairment or prodromal AD. However, practically speaking from the perspective of the “patients,” the success of such trials would amount to prevention, or at least to a reprieve before their minds start to fail them.

Newly formulated by Reiman and Tariot, the vision of drug trials for pre-symptomatic AD was previously considered too difficult to realize (for ostensible reasons, see ARF essays on eFAD prevention trials). “This was a pipe dream not long ago,” Tariot said. Now, its time may have come, industry and academic leaders agreed in Phoenix. To a reporter who has covered the issue before, the change in tone was striking. As recently as two years ago, when industry scientists were asked about testing their most attractive candidate therapy in prevention trials, a positive reply would go along the lines of: “We would like to do this but…”, and then a conversation about problem after problem would ensue. More typically, pharma scientists would simply point out that their senior management would reject such trials because it viewed the risks to the candidate drug and the company’s investment in it as exceeding the potential benefit. Last month, however, AD program leaders from company after company greeted the API proposal positively. This article will not attribute quotes by industry scientists to protect open discussion at forums such as the one in Phoenix and to avoid the need for lengthy internal review by corporate communications. Here are unattributed samples of what they said about the proposed initiative:


“Prevention is where we have to go.”

“The time is right.”

“I am very encouraged— for years we have wanted to do this kind of study in genetic populations.”

“This is the right thing. That it is difficult is just part of it, and we will try to work that through.”

What has changed? Several trends are coming together. For one thing, imaging and biomarker data generated by ADNI as well as by observational studies in Reiman’s and other centers worldwide have converged to a degree of consensus; they support planning pre-symptomatic trials that rely on these biomarkers for enrollment and/or for measuring success (see ARF Webinar). Various amyloid imaging agents are in Phase 3 studies and might receive the Food and Drug Administration’s blessing before long. A worldwide Quality Control program is gearing up to make CSF Aβ/tau testing more robust (see ARF QC series). The Critical Path Institute, whose director, Louis Kirby, attended the Phoenix meeting, is working to speed up the FDA’s formal acceptance of biomarkers. AD scientists are already detecting a subtle opening on the part of FDA regulators, who are increasingly accepting the notion that the presence of AD pathology in a person’s brain prior to symptoms represents a disease state. An accelerated approval pathway based in large part on biomarker evidence exists and could potentially serve to guide the API.

At the same time, the conventional model of drug testing is being called into question as anti-amyloid and other investigational therapies have so far performed below expectations. “There is a growing concern that these may be too little too late to exert a profound clinical effect once patients have even mild symptoms. We need to move earlier,” said Reiman, and this stance now draws widespread support. In Phoenix, one company scientist recounted how the trial results of anti-amyloid drugs played internally at his company: “The weak trial results hit the hypothesis hard. In 2009, we were asked to present to senior management on the state of the amyloid hypothesis, and the outcome of that was that the best test of the hypothesis were prevention trials both in PS1 and in ApoE4 high-risk groups.” This resonates throughout industry as scientists are preparing internally for what to do next once their present crop of experimental treatments has completed the current round of clinical trials.

This is not to say that researchers are giving up on the effort to treat symptomatic patients; large trials are continuing and hope is still high that some investigational medicines will show an effect alone or in combination. But at the same time, there is a growing sense among scientists that many of the currently known treatments may be most beneficial early in the process.

Specifically, scientists in Phoenix noted that the field is undergoing a paradigm shift whereby treatment of mild to moderate AD might require other classes of treatment (read: non-amyloid ones, because by then the disease has become independent of this pathology) than treatment of the preclinical period, where anti-amyloid investigational therapies seem more closely linked to the disease process. “We are in the middle of a sea change in AD realizing that,” one pharma representative said.

Finally, public awareness of AD is growing, along with a sense that research participants at high risk for AD deserve access to the most promising drug candidates (see ARF eFAD essay).

Despite the main news at this juncture—unison advice by industry to press ahead—readers should not expect to sign up for a prevention trial just yet. There are still plenty of obstacles to clear. The list includes drug safety, dose determination, trial design, genotype disclosure, among others. The 26 January 2010 meeting in Phoenix followed an earlier gathering of academic scientists, representatives of federal and private funders, and related groups that Reiman and Tariot had called in October 2009. There, too, the motto of the day was not to let challenges deter the overall initiative. “The issues have reached a stage of clarity where we must move forward even without complete consensus on how to solve these big remaining problems,” concluded Paul Aisen of the University of California, San Diego, who directs the ADCS. Things are moving. Reiman and Tariot flew to Colombia earlier this month, exploring the installation of a cyclotron there to make PET compounds for amyloid imaging, meeting scientific staff and family members, and generally laying groundwork for the screening of the initial 1,000 prospective study participants.—Gabrielle Strobel.

This is Part 1 of a five-part series. See also Part 2, Part 3, Part 4, Part 5. See also a PDF of the entire series.


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News Citations

  1. St. Louis: Scientists, Families Target Preclinical Detection, Trials
  2. Phoenix: For Shared Prevention Trials, Devil Is in the Details
  3. Worldwide Quality Control Set to Tame Biomarker Variation
  4. Phoenix: Can Alzheimer’s Prevention Initiative Break a Catch-22?
  5. Phoenix: Trials in Colombia and the U.S. for Those at Highest Risk?
  6. Phoenix: Making Trials Work for Patient, Sponsor, Regulator

Webinar Citations

  1. Together at Last, Top Five Biomarkers Model Stages of AD

Other Citations

  1. ARF essays on eFAD prevention trials

External Citations

  1. Alzheimer's Disease Neuroimaging Initiative (ADNI)
  2. Alzheimer's Disease Cooperative Study (ADCS)
  3. Dominantly Inherited Alzheimer Network (DIAN)
  4. Critical Path Institute

Further Reading