Diagnostic accuracy is not the only obstacle, however. Companies also don't like to take on added risk of unforeseen side effects. They worry that a serious side effect, let alone a death, in a young patient could doom the development of the drug for the entire AD market. There is no evidence to suggest this would happen, but a small risk always exists that a particular genetic mutation can make people prone to react to drugs differently. In essence, companies do not want to shoulder the risk that a complication in a small population could derail a product aimed primarily at a large population. In their eyes, letting a few eFAD patients into their trials raises the stakes without significantly enlarging the return. Some company scientists have said they are keeping eFAD at arm's length because they consider it such an aggressive form of the disease that it might override the action of a study drug that is helpful with the sporadic form. Others cite a basic science concern. They say that particular eFAD gene mutations might render certain drugs less effective in these patients than in the general AD population; this applies to certain changes in the presenilin gene and drugs called γ-secretase modulators, for example. How to handle genetically defined subgroups is an issue that frequently comes up in clinical trial design for other diseases, as well. It is part of the reason why drug developers say that treating someone with a drug is different from testing that drug in certain genetic subgroups. But it is a narrow scientific concern that experiments can clarify, and which does not apply in the same way to immunotherapies or to neuroprotective agents.
Importantly, these caveats are exceptions to the larger point more scientists emphasized. They said that eFAD patients may indeed be the ideal population in which to test drugs targeting amyloid-β, precisely because eFAD is a more clearly amyloid-driven form of Alzheimer disease than the late-onset form. "There is a nice opportunity in having a patient population that has a biologically true illness. Your signal detection for efficacy may be better in that population," a Merck scientist said. (Scientists from Merck requested that they not be named individually.) Company scientists cite another upside to testing drugs in younger patients. They tend to be strong and healthy, whereas older patients often have multiple accompanying health problems, such as cardiovascular or metabolic disease, which make them prone to side effects and drug interactions.
So, is the glass half full or half empty? Scientists won't know until they have included eFAD patients in trials, but companies are not being adventurous because any failure in even a small number of eFAD patients becomes part of the drug's official development record and could endanger its approval.
Scenario 2: Design Adjunct Trials of Experimental Medicines Dedicated to eFAD and EOAD
If drug developers won't allow young patients into their large trials, would they run smaller trials specifically for them? On this question, company researchers demur, saying it's too soon just yet. Some said they prefer to bring a drug to market as fast as they can and only then expand its testing to the eFAD/EOAD population to see if it works in them, as well. To a degree, this becomes an academic exercise because, once approved, neurologists can prescribe a new AD drug to patients of any age. Physicians probably will use it right away for younger patients because their situation is so dire. The benefit would largely accrue to the company by enabling it to formally expand the claim on its label to early-onset forms of AD. Indeed, given that neurologists consider eFAD and LOAD to be similar in terms of how symptoms progress, they may deem it unethical to withhold a new drug, or to test the efficacy of an approved AD drug through a double-blind, randomized clinical trial in which eFAD patients risk being put in the group taking a placebo.
When pressed about running small adjunct eFAD/EOAD trials alongside clinical trials for LOAD, scientists from pharma companies do not reject this suggestion out of hand. They acknowledge an argument put forth by a growing number of academic colleagues, who say that testing a drug exclusively in older people with sporadic disease and significant other health problems might lead a company to discard a promising drug that might well show an effect when tested in a well-characterized, early-stage patient. It is difficult to identify the earliest-stage patients, and this is where eFAD families offer a unique advantage. When you already know eFAD runs in a given family, it is much simpler to spot it early in additional relatives.
Another reason why companies have not already begun such trials is scientific. Scientists have formulas for calculating how many patients they need to enroll in order for the trial to be able, or "powered," to detect whether the drug does any good. For the most part, the number of patients needed depends on how the trial measures the drug's effect and how effective the drug is. These days, conventional clinical and cognitive measurements are still the norm—how independent do the patients remain; how do their different domains of understanding and memory fare?—even though every scientist involved bemoans their variability and other shortcomings. Phase 3 trials of prospective AD drugs (these are the late-stage, pivotal trials on which approval by the Food and Drug Administration (FDA) hinges) enroll between 1,000 and 2,000 patients because that is what the formula calls for. At present, this many early-onset AD patients are not readily available, company representatives say. (If, however, more patients were to be diagnosed at an earlier stage, through education and outreach, the numbers of potential clinical trial participants could become significant.) Scientists therefore face the challenge of designing much smaller, more experimental trials that can yield useful information with newer measures of the drug's effect.
"We know the power calculation for the true clinical endpoints. It means we need large trials. Is it possible to do small trials with other endpoints, such as imaging or biomarkers? I do not know the answer to that now. It changes as our knowledge progresses," Dale Schenk of Elan Pharmaceuticals said.
The critical ingredient to get such trials out of the gate is a surrogate biomarker, that is, some other—faster, cheaper, simpler, and above all more precise—indicator that a person's disease is progressing. Memory, cognition, and the ability to function in daily life are endpoints that take time to assess, can require subjective judgments, and indeed fluctuate over days, or even over a few hours in a given patient. It would be much better to have something more stable and objective—say a brain scan or a biochemical test on blood or, if need be, spinal fluid. Such a biomarker would be a boon to all AD clinical trials. It is hard to overstate the importance of a validated biomarker, and people know it. This research is burgeoning in academia. "The bottleneck now is applying the knowledge that has been accumulated to the practical reality of clinical trials," a senior Merck researcher said.
To be able to support a new drug application (NDA) of a candidate drug in lieu of those conventional clinical endpoints, a biomarker has to have FDA approval for that purpose. That is a high bar, and no biomarker crossed it yet. To get this approval, the biomarker needs to be "validated" within a clinical trial. The process of gathering the necessary data for that is iterative, i.e., a bit like a spiral. Here is how scientists hope this will work: a trial of drug D uses biomarker M. The drug quickly and measurably changes M in a predictable way and, later on, turns out also to improve Alzheimer disease as measured by the clinical readouts. This is an association, and it makes researchers perk up. Proof will require a couple more iterations, where drug E in a different trial also changes biomarker M and improves Alzheimer disease clinically, whereas drug F in a third trial fails to move biomarker M and later also fails to improve AD. At that point, biomarker M will come to be seen as a valid flag of whether a drug works. Until then, neither researchers nor the FDA will believe that changing biomarker M alone is good enough. After all, a drug could change the biomarker but not help with the clinical symptoms of the disease at all.
This is more than a pedantic quibble. It is a disheartening error that has repeatedly set back drug development in the cancer area, where a vaunted biomarker responded well to a drug, yet the patient still died. Or take the recent demise of Pfizer's much-anticipated cardiovascular blockbuster drug torcetrapib: its effect on the surrogate marker (it boosts HDL "good" cholesterol) first made it look like a Dr. Jekyll, but its subsequent effect on the meaningful endpoint (it increased cardiovascular problems and deaths) revealed it as a Mr. Hyde. In success stories where the surrogate marker proved its worth (see sidebar on statins, to be posted next month), its validation came about gradually through cycles like the one outlined above. Once the AD field has developed some consensus that a particular biomarker truly heralds improvement of AD, and the FDA accepts it as a predictor of a drug's impact on clinical disease, drug trials will become smaller and faster.
Here's one example of what people are watching in this context, and why it matters to eFAD. Despite its troubles, the AN-1792 trials of the first immunotherapy for AD did show that the concentration of certain forms of a disease protein called tau decreased in the spinal fluid of trial participants who appeared to have responded to the vaccine by making antibodies against it. That is only an association. What does it mean? It is tantalizing because clinical studies of eFAD have shown that the amount of this protein increases in the spinal fluid as presymptomatic carriers of the disease gene approach the time when doctors expect symptoms to show up. And some data are available to suggest that people who responded to the drug indeed did a little bit better 4.5 years later (see ARF Washington conference story). Ongoing trials of different drugs are checking if the drug at hand lowers spinal fluid tau, in addition to assessing cognition. If over the next few years a number of these investigators note a drop in tau and get a clinical benefit, then the field will anoint tau as a validated biomarker.
The reason why observational studies in eFAD families should start now is that by the time a biomarker emerges as a chosen one, the observational studies will have gathered several years' worth of data on how that marker changes in given family members. And here is the dream these families' neurologists are nursing: to stick with tau as an example, the researcher watches tau go up inexorably year after year in mutation carriers before the symptoms creep up on them. Then the field learns that tau is, indeed, a valid marker. With the data on tau in eFAD families in hand, a drug can be tried just to see if it lowers tau in their spinal fluid. If it does, then scientists could have some confidence right away that the drug actually helps stave off symptoms in a given carrier, instead of having to wait 10 more years to observe the expected development of symptoms in those carriers.
Tau is but one example of a promising biomarker. Another is a brain-imaging compound called Pittsburgh Compound B (PIB), which makes amyloid protein deposits visible in the live brain with a specialized PET scan. PIB, too, shows up long before symptoms. There is an early hint that a candidate drug both decreases PIB and gives a small clinical benefit, though the effect is small and the data are not published yet (see ARF Salzburg conference story). A biomarker trial combining a new candidate immunotherapy and PIB is underway in Europe. If several studies manage to definitively tie changes in PIB to symptoms and improvement, it could flag a drug's worth very early on indeed. Further biomarker candidates besides tau and PIB include the concentration of certain biochemical components of the CSF, the volume of certain brain regions as measured by MRI, and the activity of certain brain regions as measured by PET imaging.
Some ongoing trials of experimental drugs across the world have begun incorporating candidate biomarkers from the fields of brain imaging and blood or CSF biochemistry to answer this question. Unfortunately, few trials incorporate a broad battery of all candidate markers so that the best one can emerge from a direct and comprehensive comparison. Some trials perform one form of brain imaging but not another; others include brain imaging but not lumbar punctures, thus losing the chance to learn how brain imaging changes alongside cerebrospinal fluid biochemistry. Overall, this piecemeal, fragmented approach is slowing the identification of the best marker. Besides study participation by many more eFAD families, and better coordination among such studies, the one pressing need all scientists interviewed for this series agreed on is the need for a validated biomarker. With a marker, with data on that marker's prior behavior in an eFAD group, and with an experimental drug that looks strong in LOAD phase 3 trials, the field would be set to open a special trial for eFAD families.
Scenario 3: Give Experimental Medicines to People with eFAD/EOAD on a Compassion Basis
If scientifically sound drug trials are still some years off, is there not a way—any way—to channel promising drugs to eFAD and EOAD patients sooner? They live among us. They are losing their minds while their young families look on and struggle. They can't hope to get better. In the case of some eFAD patients, their fathers, aunts, brothers, or they themselves have contributed time, money, and pieces of their bodies to AD research. They know experimental drugs exist in vials and syringes, in freezers of companies and hospitals around the country. Yet they can't get them. Added to their burden is the tantalizing suspicion, even if it may be unfounded, that somewhere out there, one of those vials might contain the magic bullet that could save them.
In the U.S., the term "Compassionate Use" denotes a set of methods by which experimental therapeutics sometimes are made available to people before the FDA has approved them, or if the drug has been denied approval. There is no official FDA regulation or policy defining Compassionate Use. The difference between Compassionate Use of a study medication and its regular use in clinical trials is that the former serves to treat a desperately ill person based on some prior indication that the drug might prolong life, not to test the safety and efficacy of the medication. At present, Compassionate Use is reserved for people who are critically ill, typically with cancer, and who have exhausted all other treatment options. Compassionate Use often requires a case-by-case dispensation from the FDA; at other times groups of patients can receive it under a special form of permission called a "treatment IND."
This occurs against a backdrop of tension between patient advocates and the drug sponsors. The former reach for anything that could treat a loved one, and they resent being rebuffed. The latter insist on testing the drug rationally. They maintain that making a potentially toxic drug widely available before its benefit is proven and contraindications known would do the patient and the broader public a disservice. Companies resist giving out a study drug before they feel they fully understand it. To some extent, it is a struggle between an individual's control over his or her disease versus a company's control over its product development.
Expanded Access is a related term, sometimes invoked for AIDS and other drugs. It denotes a process by which drug companies make unapproved drugs more widely available beyond those relatively few patients who are formally enrolled in clinical trials. This happens, for example, in situations where the company has solved a manufacturing bottleneck and is now able to increase supply of the experimental drug. It usually occurs late in the development process when the company feels confident the drug is safe and effective. Typically, a strongly positive result in an initial phase 3 trial may prompt the company to expand access for the period of time during which it conducts additional trials to complete the formally required package of data and documentation, called a New Drug Application, to the FDA. In those cases, companies announce an expanded access program that enrolls patients, and treats and follows them under looser guidelines, often under the care of their own local physicians, than are required in clinical trials, for which patients have to come to specialized trial centers.
In early-onset Familial Alzheimer Disease (eFAD), Compassionate Use or Expanded Access have not entered the realm of serious discussion yet. Partly that's because eFAD families do not have a deft support group that advocates vociferously for them. Partly it's because no experimental AD drug has had sufficiently impressive results that make doctors want to jump through the hoops of obtaining it for Compassionate Use. "I would not know what to give," says Daniel Pollen, a neurologist at the University of Massachusetts Medical Center in Worcester, who has treated FAD families with compassion, and at times experimentally, for decades. But it's also because Alzheimer disease is a slow, degenerative disease and there is no precedent yet for adapting the current vision for Compassionate Use to it.
Company researchers are quick to point out that the analogy with cancer and AIDS is weak because patients with those diseases tend to be at death's door and would take the experimental drug for weeks, or months at most. Consequently, the drug's toxicity is a distant worry to all involved, from the patients to their doctors, the drug company and the FDA. In contrast, a person in whom eFAD symptoms are beginning to show has 5 to 15 years yet to live. For how long would they take the experimental drug? Would they take a secretase enzyme inhibitor, an amyloid buster, a microtubule stabilizer, a novel NSAID for the rest of their lives? If the drug works, that could be 20 years or—hopefully—longer. The side effects from taking a drug that long can be serious, even deadly. What if an early-stage patient dies from liver or heart problems 2 years after going on an experimental drug? What sort of safety record must a drug have before one can responsibly recommend it for this type of patient? These are important questions that must be addressed among scientists, and between them and the FDA.
Similarly, much hope in the field and among patients rides on AD immunotherapies that are currently entering early- to mid-stage clinical trials in Europe, the U.S., and Asia. At least a dozen companies are working on this approach. Researchers and doctors alike feel that their safety is not well enough proven to give them to people outside of those trials. Here, too, how much safety data is enough is anyone's guess at this point.
The issues of Compassionate Use and Expanded Access may come to the fore once a treatment performs truly well in a phase 3 trial. It is not too soon to start thinking about what the risk-benefit ratio should be for young people with EOAD. Let's stick with a previously cited example: the AN-1792 vaccine. In 2002, researchers reported that 6 percent of patients in a phase 2 trial developed inflammation of the brain membrane. The trial was stopped and the vaccine mothballed (second- and third-generation products are in trials now). A treatment with a 6 percent risk of causing a serious if not deadly side effect would never be approved, and rightly so, many will agree. But consider the patient's perspective. Suppose you are in your forties or fifties, and 100 percent guaranteed that you will lose your mind and become mute and bed-bound, probably in the next decade. Would 6 percent be an acceptable risk? It actually would, said UCSD's Leon Thal, if we knew that the vaccine works. We will never know for AN-1792. The product is dead, but it illustrates the larger point that the risk-benefit ratio for someone who faces a predictably dreadful prognosis needs open-minded discussion. What, exactly, does the Hippocratic oath of "First, do no harm" mean for an eFAD family where the harm from the predictable prognosis is already so demonstrably great?
"I am the one with the gene. From my perspective, the risk of harm from a vaccine is less severe than the risk of death," is how one eFAD carrier summed it up.
A discussion of when a drug becomes a candidate for Compassionate Use or Expanded Access should involve all stakeholders, from family representatives to doctors, drug sponsors, academic researchers, and the FDA, sources interviewed for this article said. It should deal openly with these problems. It should also address a related issue, namely, that of competition for patients. If there were a form of Expanded Access for a given drug, every eFAD patient opting for it would probably be one fewer patient to take part in scientifically rigorous clinical trials of that drug. They might also be barred from trials of other drugs. If you are in one drug trial, you cannot generally take part in another at the same time. This is typically true for the duration of the dosing and subsequent observation period afterward, and for special medicines such as active immunization, it might be true for longer. In essence, researchers and doctors learn much less about a drug when it is used in a less controlled setting in a given person than when that person is enrolled in a trial. In a situation where the number of eligible and willing patients for trials is severely limited, Expanded Access can raise thorny questions of balancing benefit to the individual against benefit to future patients.
A related problem is "trial shopping," that is, patients who drop out of one trial mid-way to join another. This is devastating for researchers, who have invested years of effort and large amounts of funding to conduct the trial. They cannot complete a drug study, nor learn much of anything, if patients refuse to stay in it the whole way and to honor restrictions about taking other medicines simultaneously. But once a potentially better drug shows up on the horizon, is it ethical for the neurologist to keep people with a genetic prognosis in a trial for a less powerful drug? Here, too, a balance between the individual and the greater good must be struck. "We have to be careful that we don't let desperation overwhelm our good judgment about not hurting people and doing proper trials," said Randall Bateman. "If you do the science loosely, just to 'see if it helps,' you don't learn anything real, and that doesn't help the individual patient or the eFAD community. I really believe we should do it right."
This hewing to scientific and medical standards can be maddening to people whose loved ones are being extinguished slowly in front of their eyes. It is no less frustrating in other diseases. For some, patients and their advocates have tried innovative ways to find strength in numbers, e.g., CancerGuide.
Perhaps the challenge to scientists is to figure out if it is possible to devise scientifically rigorous ways of making trials more flexible, for example, by allowing people to take several drugs simultaneously or in quick succession.
Scenario 4: Test FDA-approved Drugs in People With eFAD
If current AD drugs do little, and future drugs are slow to come online, why not test drugs developed for other diseases in the hope that one will prove to have a second effect on AD also? There is no open, public effort to systematically test all FDA-approved drugs in a relevant AD assay, though some company scientists claim to have long checked all of their own drugs internally, with no results. (These claims cannot be examined independently because companies do not publish these studies.) This is not to say that such an effort would be unprecedented. Advocates-turned-scientists for amyotrophic lateral sclerosis (ALS) 8 years ago started up a non-profit biotech institute that has broken new ground by testing FDA-approved drugs in an ALS mouse model and by freely publishing all its data along the way. Founded by the brother of a young ALS patient, the organization works to bring patients and researchers together around the goal of drug development. The family has spun off a company called PatientsLikeMe, through which patients and doctors can form an online community to share information about treatments they tried and to take greater control of the disease in other ways, as well. In AD, no such online collective exists, even though research estimates put the number of people with early-onset AD higher than that with ALS.
In AD, some efforts are being made with regard to existing non-AD drugs. For some neurologists, waiting for new AD drugs to wend their way through the clinical trial maze while in the meantime prescribing cholinesterase inhibitors and perhaps memantine has not seemed enough, and they have cast about for ways they can use other drugs to help their eFAD and EOAD patients. They are taking cues from the larger field of LOAD research, which has tested cholesterol-lowering statin drugs, non-steroidal anti-inflammatory drugs (NSAIDs), sex hormones, diabetes drugs, and some psychiatric drugs, among others, in older people with AD. Of those, many trials have failed, some are ongoing, but none have inspired more than modest hope. "I have seen no light bulb effects so far," says Pollen.
Some neurologists are not waiting for successful trials. They prescribe a statin, especially if a patient's cholesterol levels would warrant such therapy in its own right, along with perhaps an NSAID and either low-dose testosterone or estrogen to some eFAD patients, even some presymptomatic carriers. Their hope is that the drugs will tamp down whatever cholesterol- or inflammation- or hormone-mediated process might be fueling the progression of Alzheimer disease, and that each drug will have some small benefit that in combination adds up to be worth it. It must be said, however, that it is still not clear if these drugs really help, and they do have risks and side effects.
Here again, patients and families need to understand the distinction between being treated as a patient versus volunteering for a research study. If a patient sees a neurologist in a clinical setting, the doctor is free to prescribe any approved drug, and some are more aggressive in that regard than others. By contrast, in a research study, the same neurologists are tightly restricted in how they treat patients. In this situation, the neurologist may only do what the study protocol specifies and the institutional review board (IRB) has permitted. This is another way of trying to keep the trial population as homogeneous as possible (as noted above) and the study's interventions and assessments as consistent as possible, so as to improve the trial's chances of revealing an effect of the drug being studied.
On the trial front, statins still hold promise. Some publicly funded groups, as well as some large pharmaceutical companies, for example Pfizer, are testing statin drugs on AD patients. Among clinical studies of eFAD families, few have moved beyond observation to treating patients on a small scale. Results are not published, so other scientists in the field cannot learn from them. One is Biocard, a now-discontinued study formerly conducted at the NIMH that had enrolled some families with eFAD. The other one is an ongoing biomarker study led by Pollen (Moonis et al., 2005). It is measuring levels of candidate markers in the blood and spinal fluid of eFAD mutation carriers and their unaffected relatives, and some of those now take cholesterol-lowering statins. The rationale behind this approach is twofold. First, the scientists want to track how these drugs affect candidate biomarkers. Second, science has shown that a person's risk of getting dementia increases right along with their vascular risk factors such as hypertension and cholesterol, so treating those factors might benefit the brain, too.
NSAIDs looked like they might protect against AD in epidemiological studies, but subsequent treatment trials have failed or were halted amid safety concerns. Existing NSAIDs would likely be too toxic for long-term use in many patients at the dose needed to have a significant effect on the brain. A phase 3 trial for an unapproved, hopefully safer version of an NSAID is being closely watched (see Flurizan); if it succeeds it would become a new treatment option. Similarly, some studies have suggested, and continue to do so, that sex hormones may protect the brain, but there, too, clinical studies to date have been disappointing. Trials of diabetes drugs are still underway; current data suggest that they may help people who have inherited certain ApoE isoforms but not others (Risner et al., 2006. Note that chronic use of that drug, rosiglitazone maleate/Avandia, is being investigated for possible cardiac side effects.)
Most scientists agree that these existing drugs will at best serve as sidekicks to a future generation of medicines that alter the course of AD itself. This supporting role can be extremely valuable: in cancer and AIDS, too, combined therapy with drugs that individually have only a tiny benefit has proven to be much more powerful than each drug alone. Statins, NSAIDs, and maybe a little dab of testosterone might make a respectable supportive therapy until a truly mechanism-based drug comes along; after that they can become part of a broader preventive strategy, said Pollen.
These drugs don't aim at the bull's eye. They influence AD indirectly. Given that they tend to target processes other than amyloid production, researchers feel that LOAD is actually a better test bed for these drugs than eFAD. LOAD is more multifactorial, that is, many different age-related factors conspire to cause dementia, whereas eFAD is considered to be more purely a disease of amyloid overproduction. Because so few families are known to date to have genetically confirmed autosomal-dominant disease, researchers tend to want to keep their powder dry a while longer until a mechanism-based drug is ready for trials in them. No one believes that the families will be willing to endure a string of failures; therefore, the choice of drug will be crucial. "We will have few opportunities to test drugs in these families, especially if the drugs have toxicity. We would turn off people very quickly if a test goes badly," Thal said. Until drugs are ready, then, educating themselves and others, pressing for funding and study coordination, and enrolling in scientifically rigorous observational studies are the most productive strategies families with eFAD can adopt.
The next article in our series focuses on preventing AD. This is the Holy Grail of AD research. It is difficult to achieve. It is also where families with eFAD may have the most to offer.
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