The Dominantly Inherited Alzheimer’s Network (DIAN) was founded with the hope that its participating families could be offered a prevention trial and/or treatment trial before too long. Patients with eFAD are routinely excluded from drug trials because they tend to be younger than most trials allow and because many trials explicitly bar patients with APP or presenilin mutations. There is a bitter irony in denying drug trials to the very families whose research participation has helped open up the genetics and ensuing molecular biology of Alzheimer disease research, built countless careers in the process, and led to the development of those very drugs. This situation is finally beginning to change. Even just three years ago, leading company scientists still overwhelmingly focused on the reasons—regulatory, scientific, practical, ethical—why such trials weren’t happening (see eFAD Research section). Since then, the buzz has become noticeably more positive. Researchers across the field now openly recognize the promise of testing prevention in high-risk groups such as eFAD, and the language has changed from ‘Would be nice but can’t do it’ to ‘Want to do it. Planning how.’

For its part, DIAN was formed without industry researchers to ensure it could be independent in choosing the best candidate drugs for this small population, and its newly formed exploratory drug trial committee (see Part 1 of this series) has no pharma representatives, either. But informal consultations are going on. At the 7th Leonard Berg Symposium, Dale Schenk of Elan Pharmaceuticals in South San Francisco addressed the audience of scientists, caregivers, and early stage patients. Schenk has for years expressed an interest in finding ways to do such trials, and here, summarized, are his remarks:

“To the family members who came, I say it’s all about you. We have worked on making an anti-amyloid drug for 20 years and we hope to be right at least once, to make at least one good drug.

“Yesterday I went to the Lewis and Clark exhibit here in town and felt some kinship in what we are trying to do. They headed out on a journey not knowing what they’d find; they got hit by arrows but also had moments of stunning beauty along the way. I can assure you we are hoping for those moments, too.

“I will present to you a few considerations about potential treatment and drug trials in dominantly inherited Alzheimer disease (DIAD). They are not answers, but rather questions as we think about agents that we might consider useful in delivering to FAD patients.

“To date, most of what we do know in the clinical arena is about sporadic AD. Almost all trial paradigms are in mild to moderate AD. The entry criteria is clinical AD; we use dual endpoints—a cognitive and a functional one. And by definition, studies are clinically-based. Imaging and biomarkers are used at best as secondary endpoints, not primary ones. We need to move beyond that.

“We all want to go to prevention. How to do that? We go earlier and earlier. The next step is mild AD and those MCI cases that equal mild or prodromal AD. Most MCI trials were negative. Why? One of the key reasons, in my opinion, is that the conversion rates to Alzheimer disease were highly variable.

“The step after that is prevention of AD: that is why we are here today. Our current knowledge of potential prevention of AD comes primarily from epidemiological and long-term observational studies. One of the challenges with trying to prevent dominantly inherited AD is that we only know an average age of onset in each family but not when any given person would develop clinical symptoms. This becomes very important.

“What are the key considerations in trial design:

Who is going to be in it?
How to conduct it?
What are the endpoints?

“I’d say possible inclusion criteria for DIAD could be these: mutation carriers, age, or age relative to average age of onset for specific mutation, MRI status of change, biomarker status, PIB retention, metabolic imaging, clinical status, or combinations of the above. Each of these has problems associated with it, and we could talk about these at length.

“Then there is the complex issue of enrolling carrier versus non-carrier. How could it work if you want to be in the study but do not want to know your carrier status? One option, to enroll non-carriers in an active treatment arm, might be considered unethical. Do we know the drug is safe enough to give to non-carriers for a long time? Alternatively, individuals wishing to stay blinded can be given placebo if confidential testing shows they are non-carriers, and active drug or placebo if they are carriers.

“There are safety considerations. For example, by definition the population is presymptomatic. Risk tolerance is a complex issue for this patient group and must be assessed by the steering group, IRBs, and at the level of patients’ personal consent. Personally, I think the patients and carriers have a huge stake in this decision and should be granted autonomy to have a say in how much risk they are willing to take. It is a very individual-specific issue. Each agent has its own potential safely and efficacy issues.

“There are also pragmatic versus ethical issues. For example, for enrollment and power analysis, you need a specific age group to assess the treatment, but can you fairly exclude people at the fringes of that age group? Do you want to divide by ApoE status, MRI, PIB, or CSF? That will divide the sample into even smaller groups.

“Because of the pragmatic issues, I believe it is going to be fine to look at biomarker changes first and at clinical outcomes second. That is a very big discussion to be had, but this is my feeling about it. You could see biomarker changes in weeks to months, but the clinical outcome in a prevention study could take two to five years or longer.

“Which treatment should be considered? I can’t help but be biased here. That said, I would suggest those with at least Phase 2 safety data to have enough patient exposure to reasonably calculate their safety profile. Agents that have evidence of modifying the pathology of AD should have priority because these agents will most likely impact the most advanced biomarkers. These biomarkers will likely be impacted before clinical manifestation of the disease, and biomarker and imaging agents have greater statistical power of demonstrating a benefit with a small population.

“Should we require known efficacy in mild to moderate AD to consider a specific treatment for DIAN? Results either way may not be applicable to presymptomatic AD.

“Here’s a list of possible classes of treatment to be considered for prevention of DIAD: γ-secretase inhibitors, Aβ aggregation inhibitors, Aβ vaccines, Aβ passive immunotherapies, other neurotrophic compounds (p75). We work on those and have compounds on the way. But there are also cholinergic agents, NMDA antagonists, other neurotransmitter-related compounds, mitochondria-active compounds, tau-targeting compounds. We do not work on those.

“Some detail about ours:

  • γ-secretase inhibitors: Quite a few are in the clinic. We have a Phase 1 compound that is selective for APP over Notch. I personally think this class of compound is complex when it comes to DIAD because not every presenilin mutant may respond the same way. Our Phase 1 inhibitor has a therapeutic index of more than 65; future compounds further back in the pipeline are even higher. This bigger safety window enables a higher dose.
  • ELND005, or scyllo-inositol: This anti-aggregation inhibitor blocks the toxicity of Aβ oligomers. It is in Phase 2 for mild to moderate AD, but we have no clinical information on that trial yet. In all honesty, this is one of the few compounds that I think is very, very safe thus far. On the downside, we have not yet established that it is modulating biomarkers. With our γ-secretase inhibitor we do know that it lowers CSF Aβ42.
  • Immunotherapy: There are at least 14 to 15 different versions of active and passive immunotherapy trials in the clinic worldwide by now. There are many approaches, many sponsors, many clinical investigators working on this. We have learned a great deal. Immunotherapy can achieve real plaque reduction, and CSF tau reduction. But we do not know definitively what that means clinically in Phase 3 studies. The safety issues we ran into with AN1792 are not repeating themselves in newer trials, ours and those of others.
  • Bapineuzumab Phase 2 findings: The primary efficacy endpoints were not achieved, but post-hoc analyses of completers showed they had a cognitive benefit in that they declined less than the placebo-treated patients. The ApoE4 non-carriers seem to benefit more, so E4 might affect the treatment response. That has come up with several different drugs by now. This is why in Phase 3, separate studies are being conducted with Bapineuzumab in ApoE4 carriers and non-carriers. We have early data to say that Bapineuzumab might reduce CSF tau. On safety, the vasogenic edema is more common in treated than placebo groups; sometimes it is symptomatic. On the other side effects, the percentage of patients with serious adverse events was similar to the percentage of them in placebo. In the Phase 2 study, there were three deaths in the treatment groups that were judged as not associated with treatment.

“I can’t say which treatment should be chosen. But I suggest that the mechanism of action should be known, I do suggest using something related to Aβ, and I suggest it should have a demonstrated effect on biomarkers.

“On endpoints: I suggest choosing biomarker and/or imaging as primary endpoints, and clinical outcome as the secondary endpoints.

“How long should such a study be? The biomarker piece could take 12 to 18 months, the clinical piece three to five years. A five-year study seems reasonable.”

For more on the issue of AD prevention trials, see ARF essay and Ringman et al., 2009).—Edited by Gabrielle Strobel.

This is Part 7 of a seven-part series on presymptomatic detection. See also Parts 1, 2, 3, 4, 5, and 6.


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News Citations

  1. St. Louis: Scientists, Families Target Preclinical Detection, Trials
  2. St. Louis: The Family View—What Do Study Volunteers Want From DIAN?
  3. St. Louis: Cognition Pre-dementia—Like eFAD, Like LOAD?
  4. St. Louis: Biomarkers Pre-dementia—Like eFAD, Like LOAD?
  5. St. Louis: Is Rare Familial Alzheimer’s a Model for the Millions?
  6. St. Louis: Imaging Preclinical AD—Can You See it Coming in the Brain?

Paper Citations

  1. . Commentary on "a roadmap for the prevention of dementia II: Leon Thal Symposium 2008." Prevention trials in persons at risk for dominantly inherited Alzheimer's disease: opportunities and challenges. Alzheimers Dement. 2009 Mar;5(2):166-71. PubMed.

Other Citations

  1. eFAD Research section

External Citations

  1. Dominantly Inherited Alzheimer’s Network (DIAN)

Further Reading