Early-Onset Familial AD

Clinical Trials: Why Are eFAD Patients Excluded? Will That Change?


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By Gabrielle Strobel

Families with early-onset Alzheimer disease (eFAD) are an isolated group dispersed all over the world. See Interview: A Spouse's Perspective on Clinical Trials for eFAD. Part of their problem is that they are excluded from participating in most clinical trials by their young age. (For definitions of early-onset [EOAD] and early-onset familial Alzheimer disease [eFAD], please see What Is Early-onset Familial Alzheimer Disease?). This could soon change. These families represent an untapped resource, and researchers in academia and industry are beginning to see the potential. Publicly, companies are citing reasons why they are not testing study drugs in early-onset AD, but, at the same time, some are beginning to consider internally when and how they might do exactly that. In fact, leading academic researchers who are planning the future course of AD research have noted that it may be in the public interest to strengthen and coordinate academic investigation of volunteer families with eFAD. The goal would be to ensure that a single company does not tie up the entire small population for tests of a single proprietary treatment. A fundamental concern driving this thought is that once a person takes one study drug, he or she cannot also take another at the same time. If a person combined different experimental medications, science would be less able to learn what works and what does not, what is safe enough and what is not.

The issues are manifold. We have summarized four scenarios for the future of drug trials for EOAD and eFAD in this table.

Scenario Strengths Limitations
1. Include people with eFAD in clinical trials of experimental medicines. For mechanism-based drugs (e.g., drugs to reduce amyloid-β), eFAD may offer a clean target. If eFAD patients respond differently than LOAD patients, this could cloud the data.
2. Design small adjunct trials of experimental medicines for eFAD. It is easier to identify early-stage patients who might be more likely to respond. There may not be enough eFAD patients to give the study statistical power.
2a. Design observational studies of biomarkers in presymptomatic eFAD. Help validate biomarkers that can serve as surrogate endpoints for drug trial. None. Participants can choose whether to be told their genetic status.
3. Give experimental medicines to people with eFAD under Compassionate Use or Expanded Access. Gives eFAD patients access to treatment with a rational, albeit unproven, basis. Could offer false hope. Reduces opportunities for rigorous scientific validation of drugs.
4. Test FDA-approved drugs in people with eFAD. Offers best-guess options for modifying a disease that currently has no effective treatments. More likely to be suitable as supporting therapy than primary therapy.

Pharmaceutical and biotechnology companies are testing a range of experimental therapies for AD, and they would test even more if more willing volunteers and clinical centers with the requisite expertise were available. Most of those drugs are based around a specific hypothesis about the molecular process that results in disease. Drugs aimed at a specific molecular process are called "mechanism-based." That means scientists hope that they will actually slow the disease process itself, not merely treat the disease's symptoms, as presently approved drugs do.

Many drugs that are currently in clinical trials are mechanism-based compounds based on the amyloid hypothesis, a scientific idea that ascribes the disease to a gradual buildup and clumping together of a small protein called amyloid-β (or Aβ) in the brain. The amyloid hypothesis is not the only approach companies and public researchers are pursuing. Whether it is correct remains an open question—indeed clinical trials aim to settle exactly that. But in terms of experimental medicines one could try, the amyloid hypothesis offers the most options for patients at this point in time.

A cruel irony for people with early-onset AD is that they are almost completely shut out of such trials. Once they are diagnosed, they receive basically the same treatment from their neurologist as would an AD patient who is 25 years older. Young patients may be more eager to participate in drug trials. To be sure, trial participation does not guarantee a direct benefit for one's own disease, and most trials fail. But it means at the very least that the patient can contribute to the search for a cure. Young patients in the early stages understand very well what is happening to them. They are vigorous and often ache to be an active part of the solution. Yet as a rule, treatment trials require that the patient be at least 50 or even 55 years old. People who are diagnosed at, say, 45, must let the disease ravage their brain for 5 more years before they can join a treatment trial. The doctor, the patient, and the drug sponsor all know that by then, many more nerve cells will have died and the brain will have shrunk to a point where it is less likely to respond to an experimental drug than it might have if the drug were given sooner. Alzheimer disease advances predictably and inexorably. Everyone agrees there is no point to the conservative approach that doctors use for self-limiting diseases. No one argues that a 5-year wait equals anything but a 5-year loss of opportunity.

For carriers and their families, this kind of reverse age discrimination is frustrating. It condemns them to wait passively when they want to engage in a trial to fight the disease on behalf of their siblings or children. For neurologists, too, particularly physician-researchers who study AD drugs at academic institutions, this situation creates a painful bind. "We are in a position where we study families with eFAD and where we are simultaneously testing anti-amyloid drugs on other people, but we cannot enroll these eFAD families in the drug trials because they are not eligible," said Randall Bateman, a neurologist at Washington University in St. Louis, Missouri. "Most of our patients with eFAD are not eligible to participate even though they want to."

Why do clinical trials sideline EOAD patients? Conversations with researchers from companies and academia painted a picture of a fragmented system with constraints on all sides. Part of the problem lies in insufficient awareness and thought about EOAD, but this is changing. Another part lies in strategic considerations and in true logistic and scientific obstacles. Here, too, change is possible, and families as well as doctors can push to make it happen. Regulatory obstacles are holding back companies and academic investigators, as well.

Here are some of the major themes that emerged: scientists from different companies say in unison that they want to see all people treated, but they emphasize that testing efficacy and safety of a candidate drug is a much different process than treating a patient. But even as they rattle off a list of difficulties of testing drugs in eFAD, they leave the impression that they are beginning to consider the issue more seriously. Amid the obstacles to drug trials in eFAD, companies are increasingly recognizing the opportunities, as well. "It is not that various sponsors are not discussing it. They are," said Dale Schenk of Elan Pharmaceuticals. "We have real and practical difficulties in approaching it. The question is how and when to do it." Some companies declined to be interviewed for this series, but, according to researchers in the field, even they are quietly exploring academic-corporate partnerships for future drug tests in eFAD. "Companies are interested in principle in the idea of testing, for example, their γ-secretase inhibitors in these families," said Peter Davies, who directs the Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders in Manhasset, New York.

As companies start to pay serious attention, eFAD families may in several years go from being rejected to becoming sought-after research subjects. At a recent conference about the future of AD research at the National Institutes of Health, leading academic AD researchers said that the time has come to begin planning a shared effort whereby collaborative groups of public-sector researchers can engage eFAD families in trials.

In a detailed essay, the Alzforum has laid out issues that are holding back various possible forms of drug testing today, as well as the pieces that need to fall into place to make them possible in the future. In summary, here is what company scientists have said:

They are unwilling to stake the fate of an experimental medicine on eFAD. It represents a small sliver of the market they hope to treat.

They are willing to consider small, experimental trials of their drugs in eFAD families, for example, in biomarker studies.

They will be very interested in testing prevention with a new drug after it is approved for the common form of AD.

They are loath to "just treat" individuals on a compassion basis. They don't want to give out an unproven drug without proper safeguards and scientific monitoring. They prefer formal trials that teach them about their drug.

They want to pave the way for drug trials with data from research observing the natural history of presymptomatic and early-stage eFAD.

This last point is the one that scientists from across different academic and commercial institutions emphasize as the take-home message of the year 2007 for everyone involved with eFAD. They all agree that now is the time for families to consider enrolling in observational studies. Well-designed studies of this kind are underway, or getting started, at several academic institutions (see Essay 7 for details). The news here is that until recently, most such studies were small, limited in scope, and conducted in isolation, but now more comprehensive studies are becoming available, and some of the smaller studies are coordinating more closely with one another.

Participation in observational studies lays the groundwork for future treatment trials. Observational studies need to run for some years to collect a knowledge base on eFAD families. They address questions such as, how do biochemical components in people's body fluids change as they approach the stage when symptoms will appear? What changes can be seen by brain imaging? Which of these "markers" truly reflect the disease? Which are just coincidental? Which of these markers can tell us whether a drug is working? Short of waiting years to measure changes in a person's memory, how else can we know a drug is useful? Where is each family member in terms of those markers relative to their AD symptoms?

"Intervention trials should wait a few more years until these observational data are in," said John Ringman of the University of California, Los Angeles, who works extensively with eFAD families.

The careful characterization of as many families as possible with eFAD is a priority for the next few years. It's important to emphasize that study participation does not guarantee access to a future treatment trial. The academic scientists interviewed for this series do not have a drug trial up their sleeve, and all hastened to add that luring people into studies with that promise is unethical. It is possible that some study participants who generously donate their time, and subject themselves to blood draws, spinal taps, and hours in a brain-scanning machine, may end up being too advanced in their disease by the time a drug trial becomes available. Even so, participating in observational studies is in families' interest because the disease is heritable. Families who want to be active say they draw comfort from fighting the disease. They know that their research participation can help make drug trials happen faster, if not for them, then for others. It also puts them in contact with the right people so they will hear of planned trials as soon as possible (see Where to Turn for Research: Human Studies of eFAD for details).

Because eFAD families with known mutations are rare, cooperation among researchers is in everyone's urgent interest. The late Leon Thalled the Alzheimer Disease Cooperative Study (ADCS, a federally funded network of academic centers that conduct AD treatment and prevention trials). Shortly before his accident, Thal summed up the situation this way: "If we in academia do not study these families, a pharma company will. They will sequester them for a trial, and the information may never become public. This should be done in a collaborative way. We need to identify the families, characterize them, and track their progression before we propose a treatment or, better yet, a prevention trial to them."

For more detail on drug trials in eFAD, see Drug Trials in Early-onset AD.