New Generation Alzheimer's Drugs: Do They Work?

Contributed by: Dennis Fortier, President, Medical Care Corporation

We've all been hopeful that a new class of Alzheimer's drugs (monoclonal antibodies) would soon bring effective treatment to the growing number of Alzheimer's patients.

The latest approach is based on using antibodies that bind with harmful amyloid protein.  The idea is that the antibodies will be naturally flushed from the body by the immune system, and take the harmful amyloid away as well.

Major trials have now concluded on two such drugs: Bapineuzumab and Solanezumab.  The primary outcome measures of these trials were "improved cognition" and/or "improved function" versus a placebo group.  That is to say, if subjects who took these drugs had either better cognition or better physical ability to perform daily activities, compared to subjects who did not, then the drugs were probably effective enough to be approved by the FDA. On these measures, all trials have failed.

But that is not necessarily the end of the story for either drug.

A secondary analysis, performed on a combination of the data from the multiple Solanezumab trials, shows a small improvement in cognition among treated subjects.  It is a weak signal, but it provides some hope on which to build.  Especially noteworthy is that the positive effect was most evident in the earlier stage patients with healthier brains.

A stronger signal has come from a look at the targeted biomarkers (amyloid and tau proteins) that these drugs target.

Researchers have speculated (and common sense has suggested), that using such drugs to remove amyloid from the brains of subjects who have already suffered a fair amount of brain damage, may not be helpful.  The obvious experiment would be to remove the amyloid at an earlier stage, before brain damage occurs, which is before symptoms of memory loss and other cognitive decline are noted. This makes intuitive sense and is well-aligned with the possible effect detected in the Solanezumab trial on early stage subjects.

As such, a key indictor of the true potential for each drug may be actual measures of amyloid reduction in those subjects who were treated.  Researchers involved in the Bapineuzumab trial announced yesterday that the drug did in fact dramatically reduce amyloid in the brain and spinal fluid of trial subjects.  Similar biomarker data from the Solanezumab trial is expected in the coming weeks.

Overall, we wish that the drugs had produced great improvements in cognition and function.  While those goals were not met, it is encouraging to note that some, small measure of cognitive improvement may have been realized in the Solanezumab trials, and a clear reduction in amyloid protein was seen in the Bapineuzumab trials.

This leaves us with a hopeful hypothesis that, if used on subjects at an earlier stage of Alzheimer's disease, before extensive brain damage has occurred,  either or both drugs may yield more effective treatment than what is currently available.

Alzheimer's Drugs in the Pipeline

Contributed by: Dennis Fortier, President, Medical Care Corporation

Recent history has not been kind to R&D efforts aimed at developing new Alzheimer's drugs.  While four approved drugs can help manage symptoms of the disease, and perhaps slow its progression to a small degree, the field has aggressively pursued new treatments that can significantly slow or stop progression.

These efforts have been hampered by the complexity of the disease and by, what most experts consider, a fairly rudimentary understanding of its pathology.  We understand that Alzheimer's disease manifests as a decline in cognitive function, and that the decline is caused by a loss of brain cells and the connections between them.  We also understand that an accumulation of amyloid proteins in the brain, and a chemical change in Tau proteins (phosphorylation) in the brain, are major factor contributing to that loss of brain cells.

However, the picture becomes less clear when we try to identify the many possible processes that start the pathology.  The answer may be related to cell metabolism, to brain chemistry, to inflammation, or trauma, just to name a few of the leading areas of scientific inquiry.  Probably, a host of these processes interact and lead to a cascade of biological responses along the way.

The questions to which we do not yet have solid answers are: which processes matter most, are they inter-related, and why do they lead to this disruptive outcome?  Without those answers, it is difficult to develop drugs that will target the right process, at an early stage.  It is a very complex problem involving the most complex of organs.

Nonetheless, research persists and scientific efforts are ongoing.  At this point, several promising agents are moving along the pathway in FDA clinical trials.  A good overview of the Alzheimer's pipeline was recently published by Fierce Biotech.  It is slightly technical, and geared toward financial analysts, but it is comprehensive and gives a good foundation of the theory behind each approach.

Bio-Markers for Developing Alzheimer's Treatments

Contributed by: Dennis Fortier, President, Medical Care Corporation

It's been a long time coming, but the FDA might finally have enough evidence to allow bio-marker measures into clinical trials for Alzheimer's treatments.  This change could potentially speed the trial process, reduce the risk of failed trials, and yield new AD therapies in the near future.

Based on an analysis of prior publications about bio-markers for Alzheimer's disease, an expert panel convened by the Alliance for Aging Research and the FDA, found ample scientific evidence for including changes in bio-markers as outcome measures in FDA clinical trials.  This means that, rather than relying solely on measures of cognition and function (which are measures of worsening symptoms), a drug could now be approved based on its ability to prevent pathological changes that are only evident through an examination of bio-marker measures.

An obvious precedent for this approach comes from the cholesterol field.  Since high cholesterol is a condition with no immediately apparent symptoms, a trial based on symptomatic improvement would always fail.  To approve cholesterol reducing drugs, the FDA allowed trial designs that used blood-based measures of cholesterol as a bio-marker, in lieu of any symptoms produced by a high cholesterol level.

It has long been known that Alzheimer's disease is characterized by a series of pathological changes.  These changes progress from shifting protein levels in the spinal fluid, then to lesions in the brain, and eventually to brain atrophy.  However, the precise relationship between the disease and these pathological changes had not been well enough understood for the FDA to allow their measures as part of a clinical trial.  With a massive research focus over the past five years and what appears to be an objective, expert review of the evidence, it appears as though future trials may well include bio-marker measures as critical trial outcomes.

Many Alzheimer's related stories get massive press coverage, despite minimal importance in the grand scheme of our efforts to thwart the disease.  This story has been relatively uncovered in the mainstream, but might well be one of the most important stories of the year.

A Blood Test Predicting Rate of AD Progression

Contributed by: Dennis Fortier, President, Medical Care Corporation

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This study out of Johns Hopkins, showing that a blood test might be useful in predicting the rate of cognitive decline in Alzheimer's disease,  is being widely covered in the press.  Here are some thoughts on the new science and what it might mean.

First, as the authors admit, this is very early stage work that has not yet been properly validated.  Second, if the research is eventually validated, that would be only the starting point for the long product development process prior to the day when a physicians might have a test they could use in practice.  Third, predicting the rate of progression may have some benefits, but if those benefits cannot be cost justified, then such a test might never be developed by any commercial interest.

I generally write optimistically in this space about new technologies and scientific advances that portend better care in the Alzheimer's arena.  In this case, I am surprised at the amount of mainstream coverage that has been afforded such an early stage study with (in my opinion) dubious clinical value.

On that note, I think there is a very interesting aspect to this research.  Given the massive recent investments in clinical trials to test agents for treating Alzheimer's disease, having a better understanding of each subject's propensity for cognitive decline could be highly valuable.

In a typical clinical trial, we apply a treatment to one group and a placebo to another group, then we look for differences in pre-determined outcomes.  In the future, if we could segment the research subjets into groups based on their expected rate of cognitive decline (slow, medium, and fast), as this new blood tests suggests is possible, then we might more clearly detect a treatment effect by comparing expected decline with actual decline.

In this regard, I think a blood test for predicting the rate of cognitive decline in Alzheimer's patients, if validated and commercialized, could play an important role in the effort to develop new solutions to the looming Alzheimer's epidemic.

Promising Alzheimer's Drugs on the Horizon

Contributed by: Dennis Fortier, President, Medical Care Corporation
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While we often emphasize the importance of non-pharmacologic therapies for treating Alzheimer's disease, more effective drugs could have an enormous, positive impact on our ability to combat its looming threat. A such, here is a brief summary of three of the most promising treatments in the FDA pipeline.

All three of these agents operate on the amyloid hypothesis which holds that, an accumulation of beta-amyloid, a naturally occurring protein in the brain, is the cause of Alzheimer's disease. While two recent trials on agents developed to reduce the production of beta-amyloid have failed, these three are intended to remove beta-amyloid from the brain.

Two similar drugs are Solanezumab and Bapineuzumab. Both are anti-bodies that attach to amyloid and then carry it away when they are flushed out of the body by the immune system. Solanezumab most likely operates outside of the brain which may lead to better tolerance than Bapineuzumab, which had more evidence of efficacy in its earlier stage studies. Each trial is well underway and the first published data should be forthcoming in late 2011 or early 2012.

Gammagard is Baxter's intraveneous immunoglobulin or IVIG, which also relies on removing amyloid through immune system mechanisms. IVIG is already on the market but with no approved claims for treating Alzheimer's disease.

There are certainly other approaches in the pipeline, some of which may bring better results in a shorter time frame than the three highlighted here. But these seem to have the strongest theoretical underpinnings and have bred the most optimism in the scientific community.
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A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share buttons below to spread this educational message as widely as possible.

Alzheimer's Researchers Need Volunteer Subjects

Contributed by: Dennis Fortier, President, Medical Care Corporation
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We all agree; rapid scientific advance in the field of Alzheimer's disease will be the only way to avoid a joint crisis of declining senior health and an underfunded public health system in the coming years.

One barrier to such rapid advance is completely within our control. It requires no brilliant insight or penetrating scientific discovery; it merely requires volunteers.

Enrolling research subjects into the many ongoing trials, and the many new trials expected to open in the coming years, is a timely process. In fact, the enrollment stage of a study can take years. This is a terrible waste of time in the race to save the generation that is now entering the high-risk years for Alzheimer's disease. We need to do better.

The National Alzheimer's Association has launched the Trial Match program to help interested volunteers find a study that might be right for them. I encourage you to share this with anyone you think might benefit from the information.

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A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share button below to spread this educational message as widely as possible.

Are TV Advertisements for Aricept Misleading?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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According to the FDA, they are.

Aricept is the most commonly prescribed treatment for Alzheimer's disease. It is indicated for treatment of mild to moderate dementia of the Alzheimer's type and data from FDA clinical trials suggests that it is more effective in relieving symptoms than in delaying the underlying disease.

However, recent television advertisements sponsored by Eisai (manufacturer of the drug) and Pfizer (US distributor of the drug) depict adults first meeting with a doctor, accompanied by an apparent caregiver, and then later engaged in daily activities such as gardening and caring for pets. In the opinion of the FDA, these ads suggest a level of improvement that is not supported by clinical data. The ads are currently suspended while the companies respond to the FDA's complaint.

Whatever the outcome, it is important to understand the treatment efficacy of cholinesterase inhibitors (the class of drugs to which Aricept belongs). Data from the FDA clinical trials suggest a symptomatic benefit and ongoing analysis of those data indicate a small but discernible disease delaying effect for some patients, especially those who begin treatment at an early stage of the disease. Importantly, it is now well established that a cholinesterase inhibitor combined with Namenda (a partial glutamate antagonist) yields the most benefit over the longest treatment period.

New Dimebon Trials Launched

Contributed by: Dennis Fortier, President, Medical Care Corporation
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As we have chronicled in past posts, there are multiple agents for treating Alzheimer's disease in the FDA pipeline. One of the most advanced, and by many measures, most promising, is Dimebon.

The co-developers of this agent (Pfizer and Medivation) have announced two additional trials that are now enrolling subjects. While it is not completely understood, Dimebon appears to have a novel mechanism compared to the currently approved drugs Aricept, Razadyne, and Exelon, all of which are cholinesterase inhibitors and Namenda, which is a glutamate blocker. The mechanism is theorized to be one of improving mitochondrial function to promote ongoing cell health. The new trials will explore poly-therapy with Aricept and with Namenda.

To learn more details and to inquire about enrolling in the studies, please follow these links to the CONTACT study (or email contactstudy@medivation.com) and to the CONSTELLATION study (or call 1-877-377-4476).

When Can We Expext a Cure for Alzheimer's?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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There is no definitive answer to this ubiquitous question. The best we can do is to watch the advance of science through the published literature and to follow the clinical trials from which the answer will one day emerge.

While the pathology of Alzheimer's disease is still not well understood, scientists have developed a host of well-grounded theories. Several treatment agents, based on those theoretical foundations, are currently in development or in clinical trial. Here is a short summary of the three leading treatment hypotheses:

The Cholinergic hypothesis proposes that AD is caused by reduced function of a certain chemical in the brain called acetylcholine. The chemical is known to be important in memory formation and brains of patients with AD have less acetylcholine. In fact, most medications currently approved for AD act by increasing acetylcholine levels in the brain. However, their ability to treat the disease has been limited, indicating other factors at play.

The Amyoid Hypothesis states that a buildup of deposits (amyloid) is the fundamental cause of Alzheimer’s disease. It is a compelling theory because a gene associated with this form of amyloid is located on chromosome 21 and people with an extra copy of this gene (those with Down Syndrome) almost universally exhibit AD by 40 years of age. Also, APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, amyloid buildup precedes clinical AD.

The Tau Hypothesis encompasses the idea that tau protein abnormalities form damaging tangles inside nerve cells. When this occurs, the cell's transport systems disintegrate and malfunction which may disrupt communications between cells and later cause cell death.

While these are the primary theoretical drivers of drug development, there are other agents in clinical trial that were not developed on the basis of a particular theoretical approach to the disease. Dimebon, currently in Phase III FDA trial is a pre-approved antihistamine that was shown to correlate with low dementia prevalence. Although scientists are not sure how or why it might effectively treat Alzheimer’s disease, results of the Phase I and II trials were positive and Dimebon may in fact be the next approved treatment for Alzheimer’s disease.

While it is premature to say that a cure is imminent, it should be clear that several treatment agents are in advanced stages of clinical trial. However, predicting the results of these trials is hampered by our vague understanding of what causes Alzheimer's Disease. On the bright side, one or another of these agents may be surprisingly effective in altering the disease course and could be available in two to five years. On the dark side, they may all turn out to be ineffective in which case we would be more than five years away from a meaningful new medication. Only time will tell.

In the meantime, we all need to be proactive in identifying and managing our risk factors for cognitive decline and physicians must be vigilant about acting on evidence or suspicion of decline among their patients. Until better treatments are discovered, we must intervene as early as possible with the current medications to maximally delay the progression of Alzheimer's disease.

Remember, we need a cure but there is much we can do while we await its arrival. Current treatments are more effective than many headlines suggest. With early intervention and a robust therapeutic regimen (including physical exercise, mental and social activity, a healthy diet, and currently approved medications), we can already meaningfully delay the progression of this terrible disease.

Update on Dimebon Trials

Contributed by: Dennis Fortier, President, Medical Care Corporation
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As new agents for the treatment of Alzheimer's disease move through the pipeline of clinical trial, we try to highlight milestones and announcements to keep you informed. We have written several times about Dimebon which is one of the most promising agents currently under development.

As pointed out recently by readers in Australia, the Dimebon trial is now enrolling patients down under. More information about that activity can be gathered through the Dimebon Australian Study blog.

How Can We Develop Alzheimer's Drugs faster?

Contributed by: Dennis Fortier, President, Medical Care Corporation
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One of the barriers to faster drug development is the time it takes to recruit well-characterized research subjects into a clinical trial.

Consider this example: if a trial needs 2000 people over the age of 65 who have been diagnosed with mild to moderate Alzheimer's then it is drawing from a total pool of no more than 2-3 million people in the USA. If the protocol excludes research subjects who are currently taking a cholinesterase inhibitor (the most common class of prescription drugs for AD), then the pool is cut approximately in half. Additional common exclusions for other diseases and/or treatments reduce the target population further. Seeking 2000 people from a national pool of a million or so, while in competition with more than a dozen other trials who wish to recruit the same people is a daunting task. It can take a long time.

Sadly, there are people who wish to enroll in trials but are unaware of them. Despite the efforts of the drug development groups, it is impossible to blanket the country with perfect information in real time. There is always a knowledge gap between the needs of the clinical trialists and the information held by the public.

Pfizer is taking what seems to be an intelligent step in the direction of solving this problem. They are preparing to launch a website where potential research subjects can register and share personal, medical information about themselves in a protected environment. From this database, clinical trialsts will be able to more efficiently identify and contact those subjects who would qualify for a particular trial. Hopefully, this electronic marketplace will reduce the lag between the initiation of a trial and the time when it is fully enrolled.

I expect that many will not trust a pharmaceutical company to hold their medical information without trying to exploit it for some commercial benefit. However, I suspect many others, who are keenly interested in gaining access to experimental drugs, will be willing. Pfizer and the rest of their brethren have tremendous incentives (including legal incentives) to use this information only for its stated purpose and I believe they will.

Overall, I think this is a great idea that could meaningfully accelerate drug development and produce the better AD treatments that we so desperately need.

A better understanding and more awareness of Alzheimer's related issues can impact personal health decisions and generate significant impact across a population of aging individuals. Please use the share button below to spread this educational message and help the world.

Alzheimer's Drug Development by Eli Lilly

Contributed by: Dennis Fortier, President, Medical Care Corporation
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There seems to be a bit of confusion about the various drug trials currently underway by Eli Lilly. Here is a brief summary of their activity:

The IDENTITY trials are enrolling patients aged 55+ in over 30 countries including the USA. The compound in these studies is a gamma-secretase inhibitor that is hypothesized to reduce the accumulation of amyloid plaques in the brain.

The more recently announced EXPEDITION trials are enrolling patients aged 55+ in 16 countries including the USA. These studies are measuring the potential effects of an anti-amyloid monoclonal antibody (Solanezumab) delivered via intravenous infusion.

More details about each trial including how to inquire about enrolling can be found in this announcement from Eli Lilly.

Dimebon Study Fully Enrolled

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Medivation, Inc. has announced that the phase III FDA trial for Dimebon is now fully enrolled.

This is encouraging because the full enrollment was achieved briskly at a time when many trials are competing for the same patients. Overall, it indicates rising interest and increasing optimism about treatment options for Alzheimer's disease.

Dimebon, which we described in earlier posts, is manufactured by Medivation and, if approved, will be jointly marketed with Pfizer.

Solanezumab: Information on the Clinical Trial

Contributed by: Dennis Fortier, President, Medical Care Corporation
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The phase III clinical trial (EXPEDITION2) for Solanezumab is now open and enrolling patients.

Participants must be over the age of 55, be diagnosed with mild to moderate AD, and have an MMSE score of 16 through 26 in addition to a few other criteria (here) related to other health conditions and medications.

This is the third of three interesting drugs in phase III right now (Dimebon and Bapineuzumab) that could take us much closer to effective treatment for Alzheimer's disease.

Solanezumab – Another monoclonal antibody reaches Phase III

Contributed by: David Geldmacher, M.D., Medical Director of the Memory Disorders Clinic at the University of Virginia.
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On May 21, Eli Lilly and Co. announced that a Phase III Trial of their agent solanezumab, also known as LY2062430, would begin enrollment.

In Lilly’s Phase III program, a total of 2000 patients with mild to moderate AD are expected to receive either a 400 mg infusion of solanezumab or a placebo once every four weeks. Each research volunteer will participate over about 19 months. The overall trial is anticipated to be completed in mid 2012.

On first pass, this agent would appear to be similar to bapineuzumab which is already in Phase III trials being carried out by Elan and Wyeth. There are molecular differences between the two monoclonal antibody lines, which suggest that solanezumab acts primarily outside the brain to sequester soluble amyloid beta peptide in the peripheral circulation. If true, this would predict a lower risk for toxic events in the brain, like the vasogenic edema (brain swelling) reported in Elan’s Phase II trials.

On the other hand, a site of action outside the central nervous system might mean lower overall potency. Given the small absolute effects seen with bapineuzumab in its Phase II trial, lower potency would not bode well for solanezumab’s effectiveness. Of course, all anti-amyloid immnunotherapies depend a great deal on the validity of the amyloid hypothesis.

At a practical level, participants in the solanezumab trial will receive infusions every four weeks instead of the quarterly regimen for bapineuzumab. This will triple the risk for infusion related complications, and places a higher burden on patients. If approved under their current regimens, costs of drug administration would also likely favor the agent requiring the fewest number of infusions. However, a dramatically greater effectiveness would go a long way to off-setting increased treatment costs.

Bapineuzumab: Phase III Trial Information

Contributed by: Dennis Fortier, President, Medical Care Corporation
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A Phase III clinical trial for Bapineuzumab, described in an earlier post, is open and enrolling patients.

The study is seeking subjects aged 50 to 88 with a diagnosis of probable AD. Importantly, subjects will also need a caregiver who is willing to be meaningfully involved in the study.

This drug is administered intravenously and the study protocol calls for 15 infusions over a 65 week period. More details are available here.

Bapineuzumab

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.
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Bapineuzumab is an antibody to the beta-amyloid plaques that are believed to underlie Alzheimer's disease pathology. It is currently in a Phase 3 clinical trial, which is the final step towards obtaining FDA clearance. The drug is thought to be promising because it uses a novel approach for treating AD.

In most patients, the immune system detects the presence of the abnormal beta-amyloid protein and tries to remove it. However, in AD patients, the immune response is not sufficient to remove all of the beta-amyloid, and hence the disease occurs. Bapineuzumab is thought to act as a boost to the normal immune system's ability to remove the toxic beta-amyloid. It has been shown to be well tolerated, and initial findings from the phase 2 study have been encouraging.

Interestingly, the concept of immunotherapy has been around for quite some time and antibody treatments are becoming more common and include such treatments as:

Humira for autoimmune diseases
Avastin for colorectal cancer
Erbitux for head and neck cancer
Raptiva for psoriasis
Remicaid for autoimmune disease
Tysabri for multiple sclerosis and Crohns disease
Lucentis for Macular Degeneration
Rituxan for Lymphoma
Herceptin for breast cancer

The future of AD treatment may someday soon include immunotherapy targeting the underlying cause of the disease, beta-amyloid.

Dimebon: Trials Planned for Huntington's Disease

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Dimebon, a potential new agent for the treatment of Alzheimer's disease, is now enrolling a Phase III clinical trial (the CONNECTION study). If you are over age 50 and have been diagnosed with AD but are not taking other prescription AD medications, you may be eligible to participate.

If interested, please visit the CONNECTION site linked above for more details.

Interestingly, Dimebon has also shown safety and efficacy in a Phase II trial for treatment of Huntington's disease. This agent is being developed in the USA by Medivation and they are currently in the planning process to conduct additional efficacy trials for treating Huntington's disease later this year. (For a review of the necessary steps to gain FDA approval, see Dr. Rafii's earlier post here.)

We will keep you posted as further news is released.

Dimebon

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.
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Dimebon may soon become the next medication approved for AD. In my last blog, I described the long and arduous path taken by any new compound until it reaches patients. It looks like Dimebon is advancing down this road quite nicely. Pfizer, and its partner Medivation just announced initiation of a 12-month, Phase 3 clinical trial called CONCERT, which evaluates Dimebon plus Aricept for AD. Dimebon is thought to protect mitochondria of neurons damaged by AD, whereas Aricept works by boosting the cholinergic system, which is injured in AD.

What's interesting is that this Phase 3 program also includes the confirmatory 6-month CONNECTION study, which builds on results of the first pivotal trial of Dimebon alone and is the last step needed for FDA approval of Dimebon as monotherapy for AD.

Results of the first pivotal clinical trial of Dimebon in Alzheimer’s disease, published in the July 19, 2008 issue of The Lancet, showed that Dimebon improved the clinical course of Alzheimer’s disease. In this randomized, double-blind, placebo-controlled trial of 183 patients with mild-to-moderate Alzheimer’s disease, patients treated with Dimebon experienced statistically significant improvements compared to placebo in all the key aspects of the disease: memory and thinking, activities of daily living, behavior and overall function. After both six months and a full year of treatment, Dimebon-treated patients were significantly better than placebo-treated patients on all key aspects of the disease.

In January 2008, the FDA stated that only one more pivotal study is required to support the approval of Dimebon as monotherapy for AD. If the results are successful, as deemed by the FDA, neurologists will have one more option in their armamentarium for treating AD.