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The Challenges
of Developing a Novel-Acting Agent for Alzheimer’s Disease One of the greatest challenges in the drug discovery arena is developing a therapy for Alzheimer’s disease, one of the conditions detailed in the Cambridge Healthtech Associates report Emerging Targets in Diseases with High Unmet Needs, by Allan B. Haberman, PhD. Following is an interview about the drug that is the subject of the largest ever clinical trial for Alzheimer’s. Cambridge Healthtech Associates (CHA): Please describe Myriad’s drug development program for Alzheimer’s disease. Dr. Hobden: The compound we are developing is called Flurizan [MPC-7869]. It is currently in a Phase III US clinical trial. It will be the largest Alzheimer’s clinical trial ever done, involving 1,600 patients in the United States over an 18-month period. The drug is being given to individuals who are also allowed to be on standard-care medicine. In fact, we encourage investigators to involve patients who are on a stable dose of a cholinesterase inhibitor, such as Aricept [donepezil]. Even though Namenda [memantine] would be off-label in this particular group of individuals, we know that it is fairly widely used in patients with mild Alzheimer’s disease, so we allow that as well. Our patient population comprises all mild Alzheimer’s cases, those who have an MMSE [Mini-Mental State Examination] score of 20 to 26 inclusive. CHA: What issues have you encountered relating to the design of your study? Dr. Hobden: The major considerations are the outcome measures used, the duration of the trial, and, of course, whether or not to allow trial participants to take other Alzheimer’s drugs. Our statistical analysis will examine the divergence of slopes between the patients on drug versus placebo to compare their rates of cognitive decline. Historically, with the symptomatic drugs, patients on the medication have a small boost in cognitive performance, yet the underlying rate of decline of the individuals in terms of their pathology is unaffected. For example, if you look after 6 months of treatment, you will see an improvement in the cognitive performance of the treated versus the placebo patient, but that slight difference is maintained throughout time. So if you were to go to 18 months, the magnitude of the difference would be the same as it was at 6 months. That is because, beyond about 6 months, the patient’s decline in performance parallels that of those in the placebo group. On the other hand, we believe that Flurizan has the potential to be a disease-modifying drug, having an effect on the underlying (pathological) rate of decline of the patient. So the slopes of decline should diverge from one another, and there should be a difference between the placebo and the treated group. We would interpret that as being indicative of disease modification. We don’t mind patients in our trial being on the cholinesterase inhibitors because we do not think that any disease modification occurs with those drugs. Their mode of action is also completely different than Flurizan’s. Therefore, it should not affect the clinical outcome at all. In terms of trial duration, I believe that all of the compounds currently approved for treatment of Alzheimer’s patients have been studied over a period of no longer than 28 weeks, probably with no more than 500 patients participating in the trials. Thus, going to 18 months is obviously a much longer test of the drug than what has been done for previous medications. The reasons why we are going to extend the trial to 18 months are twofold from my point of view. One major consideration is that various experts have said that if they saw slope divergence over an 18-month period, they would believe the drug to be disease modifying. In light of those expressed statements, our original design of 12 months was modified to 18 months. Secondly, data from our Phase II study revealed a slope divergence continuing out to 18 months. CHA: What is Flurizan’s mechanism of action? Dr. Hobden: Flurizan works according to the amyloid hypothesis. It is a selective, amyloid-beta 42–lowering agent. Biochemically, it is an allosteric modulator, rather than an inhibitor, of gamma-secretase. It changes the cleavage pattern from amyloid-beta 40 and 42 to amyloid-beta 40 and 38. Amyloid-beta 42 is the toxic amyloid that leads to neuronal toxicity and subsequent neuronal loss. Flurizan reduces the production of amyloid-beta 42 by up to 70% and causes the production of nontoxic molecules in its place. We demonstrated in mouse models of Alzheimer’s disease that we could affect not only amyloid plaque deposition but also behavior and learning paradigms. That is what led us to go into human clinical trials with Alzheimer’s patients. CHA: What distinguishes Flurizan the most from other compounds that are in development for Alzheimer’s? Dr. Hobden: A large number of compounds are in development for Alzheimer’s disease. I would say that the majority of them are symptomatic treatments or cognitive enhancers. Few compounds in development are potentially disease modifying. All of them address the amyloid hypothesis, but they have different targets in the pathway. All of these disease-modifying compounds try to affect the production of the toxic amyloid protein in one way or another. Flurizan is a selective amyloid-beta 42–lowering agent, and to my knowledge, it is the only compound of that class in clinical trials. Companies such as Eli Lilly have gamma-secretase inhibitors as opposed to allosteric modulators, and I believe that it has a compound in Phase II. Elan did a trial with a vaccine against amyloid-beta 42. Unfortunately, that trial resulted in cases of encephalitis; I think maybe 6% of the patients who developed antibodies died. The company is now using active immunization with monoclonal antibodies directed against amyloid-beta 42. Neurochem has a compound that it claims affects the production of amyloid plaque, but I don’t know its exact mechanism of action. The one thing in common is that these are all amyloid-centric approaches to disease modification. CHA: For many disease areas, you often hear that all of the companies are going after the same targets. Is there more diversity when it comes to drug development for Alzheimer’s disease? Dr. Hobden: No. I think that if you are going to take the disease-modifying approach to treating Alzheimer’s disease, then you have to accept what you believe to be the cause of the disease. I would say that, over the last 10 years or so, it has become generally accepted that amyloid protein, in particular amyloid-beta 42, is the cause of Alzheimer’s disease. Various companies have taken different approaches to try to affect either the production, the toxicity, or the clearance of amyloid-beta 42, and that’s what is seen among the different approaches. It is quite hard to find a compound that is an allosteric modulator, and that may well be the reason why we are the only company that has one. It is certainly not because others are unaware of that approach. We have seen a large number of patents published from different companies on allosteric modulators. Many companies, such as Eli Lilly and Bristol-Myers Squibb, went into gamma-secretase inhibitors, and they have reported significant amounts of toxicity associated with those compounds when used long term in patients. Therefore, they are probably less enthusiastic about those approaches now. I think we happen to be ahead of the curve, and I predict that you will see a lot of companies following in our path. CHA: Do you know when you will submit an NDA [New Drug Application] for Flurizan? Dr. Hobden: We are currently enrolling patients in our Phase III trial.. The study will be 18 months in duration, although we will take an interim look at the results after 12 months. The earliest that we could halt the study would be during the fall of 2007. From that point, it all depends on the FDA’s attitude toward fast-tracking Flurizan or granting it an accelerated review. CHA: Are there any biomarkers that are relevant to Alzheimer’s disease? Dr. Hobden: The problem with the whole of the Alzheimer’s field is that there are no validated biomarkers. We would love to establish Flurizan as a disease-modifying drug, but the only validated marker for Alzheimer’s disease is the existence of amyloid plaque in the brain, and the only way you can establish its presence is through an autopsy. Obviously, you cannot follow the progression of amyloid plaque build-up in the brain throughout the course of a clinical trial. The alternatives that people have looked at have been, for example, the presence of the amyloid-beta 40 and 42 species in plasma or CSF [cerebrospinal fluid]. Other than that, you could do MRI volumetric measurements of the hippocampus region. It is a “Catch 22” of sorts because, until you have a drug that is disease modifying, you cannot validate the biomarkers, and in the meantime you cannot use biomarkers to support the approval of a drug—the FDA has been very clear on that point. Many companies are looking at the correlation between the existence of amyloid proteins, tau, and phospho-tau in the CSF [cerebrospinal fluid] and the onset of Alzheimer’s disease. The problem with that, however, is how one defines the onset of Alzheimer’s disease. By the time that an individual begins to exhibit the obvious symptoms of the disease, he or she already has a significant amyloid plaque burden in the brain. Many would argue, therefore, that the disease had, in fact, started many years earlier, before the symptoms became apparent. It is complicated in that respect. The only things that are validated that can be used for approval are various outcome measures such as ADAS-Cog, which is a test of the patient’s cognitive performance. In addition there is an interview with a caregiver (ADCS-ADL), which asks about patients’ daily lives, whether they dress themselves, prepare lunch for themselves, and other kinds of soft outcome measures. CHA: Aside from the lack of validated biomarkers, and the problem of defining the exact point of onset, are there any other big challenges that you can think of to developing treatments for Alzheimer’s? Dr. Hobden: Another big challenge is the social stigma associated with a diagnosis of Alzheimer’s disease. The Alzheimer’s Association states that Alzheimer’s disease is the fourth leading cause of death in the elderly, falling behind heart disease, stroke, and cancer. However, Alzheimer’s disease is actually the only invariably fatal disease among those four. Not only that, but the disease’s course is pretty well known. Thus, the problem is twofold. First, people think that Alzheimer’s disease is synonymous with aging, and clearly it is not. Just because a high percentage of the elderly have the disease does not mean that it is an inevitable consequence of aging. For example, numerous autopsies have revealed individuals who died at age 100 and above who did not have any amyloid plaque in their brains whatsoever. As a second example of the stigma that is attached, in California, if a physician gives a diagnosis of Alzheimer’s disease, he or she must inform the Department of Motor Vehicles so that it can take away the patient’s driver’s license. As a result, doctors are reluctant to give a diagnosis of Alzheimer’s disease even though they know the patient has it. Also, some nursing homes will not accept patients into their care if they have been diagnosed with Alzheimer’s disease; so the same phenomenon is encountered there. For reasons such as these, Alzheimer’s is a very undertreated disease. A challenge in doing clinical trials is that sometimes you cannot readily find the necessary number of patients because doctors simply have not told them that they have Alzheimer’s disease. Thus, a large proportion of the population has Alzheimer’s in reality, but it can be difficult to find them. For example, we have had patients call us and ask if they are eligible to participate in our study. When we ask them if their physician has diagnosed them with Alzheimer’s, they say, “Well, no, but I am taking Aricept and Namenda; my doctor could prescribe me those drugs.” Their doctor simply has not explicitly told them that they have Alzheimer’s disease. For these reasons, finding the right patient population is definitely a challenge in doing clinical trials. CHA: How do you foresee things changing over the next decade? Dr. Hobden: I believe that the data overwhelmingly demonstrate that amyloid-beta 42 is the cause of Alzheimer’s disease. A number of drugs currently in the clinic—and more will probably enter over the next 5 years—address either the production of amyloid-beta 42, its toxicity, or its clearance. I honestly believe that those drugs will result in a modification of the disease. The very clear evidence from our own Phase II trial is that the sooner you start treating the patient, the bigger the benefit that individual will realize in terms of slowing his or her rate of decline. In the short term, I do not think that the attitude toward Alzheimer’s disease will change much from, “We’ll sweep it under the carpet because it really doesn’t make any difference.” However, the sooner you can give a diagnosis, the better off the patients, their caregivers, and, ultimately, society will be. Initially, that diagnosis is going to happen with mild Alzheimer’s disease, and then it’s going to switch to mild cognitive impairment [MCI], which is probably very mild Alzheimer’s disease dressed up in a more socially acceptable name. Then, ultimately, if the drugs are shown to be sufficiently safe, they may become used as prophylaxis for high-risk individuals. The requirement behind that, of course, will be that there are predictive diagnostics of the risk of Alzheimer’s disease, in the same way that we have statin drugs now for people with high LDL cholesterol. I think that is a good model. Ultimately, you will see these drugs used as preventives against Alzheimer’s disease in certain individuals, based on their genetic or biochemical risk. CHA: What about combining different Alzheimer’s therapies in order to tailor treatment to individuals? Do you think that would be feasible? Dr. Hobden: I can certainly imagine combining drugs like Flurizan with cholinesterase inhibitors such as Aricept. For example, suppose patients have declined to a certain point in their cognitive performance, and Flurizan could prevent any further decline. In that case, it might be possible to bring them back to where they had been 2 or 3 years before by adding a cholinesterase inhibitor. In terms of combining one or more disease-modifying drugs, it may be that it could have a bigger impact on slowing the rate of decline if they worked by different mechanisms of action.
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