New Alzheimer's Drug on Horizon? A Solid Maybe...

 

Contributed by: Dennis Fortier, President, Medical Care Corporation
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A new Alzheimer's drug, being co-developed by Biogen and Easai, has completed a Phase II FDA trial with seemingly positive results. The drug (BAN2401) is a monoclonal antibody that binds to certain forms of amyloid protein, which is considered by many in the field to be a key culprit in the onset and progression of Alzheimer's disease. When the antibody is flushed out of the system, it takes the harmful amyloid protein with it. Over the past five years, several similar drugs have shown glimmers of promise before ultimately failing in Phase III FDA trials.

For perspective, Phase II studies are generally smaller (fewer people enrolled) with the purpose of determining safety for various doses of a drug along with any possible side-effects at each dose of the drug. Phase III studies are generally larger, often longer, and usually a final step prior to "market approval".

Biogen recently presented a snapshot of the data from their Phase II FDA trial at the Alzheimer's Association International Conference in Chicago. While the results showed a reduction in amyloid among subjects receiving the higher doses and a possible slowing of cognitive decline at some stages, the presentation lacked details and many questions remain unanswered.

The primary questions were related to the trial design which appeared to have lower-risk patients in the high dose group and higher risk patients in the untreated (placebo) group. If this was the case, then it would be easier to show that the treatment group fared better (perhaps on both amyloid deposition and cognition) than the placebo group. In defense of this approach, it was taken as a safety measure, not as an attempt to show efficacy through some deceptive trial design. With that in mind, the results are encouraging.

Secondarily, some in the field questioned the validity of the instrument used to measure cognition. The instrument (the ADCOMS) is a composite measure that pulls certain items from various other, well-validated instruments and combines them in a new instrument specifically designed to detect subtle changes. Given the well-documented mediocrity of the instruments historically used to measure cognitive change in FDA clinical trials,  concerns about the ADCOMS should be somewhat tempered because the new instrument may not be significantly better than previous instruments, but it is probably no worse either. With this perspective, lingering angst about the ADCOMS may possibly be over-blown.

Overall, the trial results are both PROMISING and PREMATURE. While there is reason for a fair amount of optimism, one should not carry that optimism with an unrealistic amount of conviction.

Good Sleep is Vital for a Healthy Brain

Contributed by: Dennis Fortier, President, Medical Care Corporation

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We know this intuitively. We feel foggy when sleep deprived, and mentally sharper when well-rested.  Understanding why this is true raises three very important possibilities.

New Findings
Research out of the University of Rochester Medical Center (URMC) sheds light on an important brain cleansing process that occurs during sleep in the brains of mice, and presumably, in human brains as well. The study, published in the online version of Science, describes a cleansing process that becomes very active during sleep.

It appears that a process, whereby brain cells contract to create more space between them and cerebrospinal fluid flows through the spaces to remove proteins, is ten times more active during sleep than during wakefulness. From this, we suggest the following three possible conclusions:

1. Caffeine is Not a Substitute for Good Sleep
This research suggests that the mental fog of sleep deprivation may be partially caused by an excess of proteins in the brain. If so, these proteins may be, in some way, interfering with optimal communication between brain cells. While a jolt of caffeine may increase the intensity of signals between brain cells and allow for improved mental acuity, it won't solve the problem of excess proteins that may be gumming up the communication process. In this regard, sleep trumps coffee.

2. Excess Proteins in the Brain may cause Irreversible Damage
As readers of this blog know, a leading theory about the cause of Alzheimer's disease is the accumulation of beta-amyloid proteins in the brain. Given that the brain seems to actively flush proteins during sleep, including beta-amyloid proteins, it is plausible that sustained periods of sleep deprivation could increase the risk of Alzheimer's disease.

3. Sleep Disorders may be Especially Dangerous
If the brain engages in important processes of maintenance and repair during sleep, and these processes prevent long-term progression toward neurodegenerative diseases, then sleep may me even more important to our health than we previously suspected. If you snore, or wake often in the night, speak to your physician about a sleep study.

Cancer Drug Not Effective in Treating Alzheimer's

Contributed by: Dennis Fortier, President, Medical Care Corporation

The media have widely reported on a recent study showing that Targretin, an FDA approved drug for treating skin cancer, was effective in clearing amyloid plaques from the brains of mice.  Given that the presence of amyloid in the brain is a pathological hallmark of Alzheimer's disease, many were optimistic about the potential for a new treatment.

Alas, the scientific process of duplicating results before accepting them as valid, is an important step in generating new knowledge.  In this case, three attempts to duplicate the original findings have all failed. That is to say, no other lab has been able to show a reduction of amyloid in the brains of mice treated with Targretin.

The original study with the positive result was conducted at Case Western University Medical Center and published in the journal Science.  In its latest edition, the same journal published a technical comment describing the negative results in three other labs.

Intriguing New Insight into Cause of Alzheimer's

Contributed by: Dennis Fortier, President, Medical Care Corporation

As the experts in the field readily acknowledge, they really don't understand Alzheimer's disease very well.  A new hypothesis, based on a recent publication in the Journal of Neuroscience, suggests that previous views and treatment approaches might be aiming at the wrong target.

The dominant theory (the amyloid hypothesis) is that excess accumulation of beta-amyloid, a naturally occurring protein in the brain, aggregates into toxic plaques that disrupt cell function and leads to cognitive decline.  Based on the new research, it is plausible that beta-amyloid is in fact the main culprit, but that it does its damage inside the brain cells, prior to breaking free and accumulating into plaques.

Some of the general press on these findings have described the science as a complete contradiction of the amyloid-hypothesis.  In reality however, it is fairly consistent with one important difference.

The new insight is that beta-amyloid might be causing harm earlier in the biological process than previously believed.  This study suggests that once the beta-amyloid has been dispensed from brain cells and clumps together into a plaque, the damage has already been done. Previously, it has been theorized that the formation of the plaque is the beginning of a toxic biological process.

The implications for treatment are that we should be looking to reduce the presence of beta-amyloid inside the cells, as opposed to clearing it away later, once it has aggregated into a plaque. Fortunately, two of the most promising agents in the FDA pipeline, Bapineuzumab and Solanezumab, are both antibodies that bind to beta-amyloid and clear it away through the natural immune function. It is hoped that one or both of these agents might function at the early, biological stage suggested by this new insight.

New Insights into the Cause of Alzheimer's

Contributed by: Dennis Fortier, President, Medical Care Corporation

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Last month, a publication in the journal Science suggested a potentially important nuance to our understanding of Alzheimer's pathology.

The most prominent theory in the field, the amyloid hypothesis, posits that excess beta-amyloid in the brain forms plaques which eventually kill brain cells and impair cognition.  However, the cause of the excess beta-amyloid is an open question.

The new study, from the University of Washington, suggests that the excess is not due to over-production but by poor clearance of amyloid.  The study, on just 24 subjects, twelve of whom had Alzheimer's and twelve of whom were cognitively normal, showed that the subjects with Alzheimer's produced beta-amyloid at about the same rate as the control group but cleared it into the blood stream about 30% slower.

If further validated, this finding could lead researchers down a more well defined path in their efforts to discover new treatments for excess amyloid in the brain.

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Bio-Marker Diagnostic Test for Alzheimer's Disease

Contributed by: Dennis Fortier, President, Medical Care Corporation
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Researchers at the University of Pennsylvania have published in the Annals of Neurology the development and standardization of a test to accurately diagnose Alzheimer's Disease (AD) by measuring the levels of beta-amyloid and tau protein in the spinal fluid. While many news stories are forwarded to me on a daily basis, I sense a particularly high level of interest in stories such as this one.

My primary take on news about bio-marker diagnostic tests is two-fold.

First of all, it is tremendously positive in the following sense. We are currently detecting patients with AD, on average, when they have end-stage pathology (up to 95% of patients are detected 8-10 years after the onset of symptoms according to published data). One of the reasons we intervene so late is that many physicians believe (erroneously) that a brain biopsy is the only reliable method of establishing a certain AD diagnosis. While it is true that a brain biopsy is one certain diagnostic method, following the published NINDS-ADRDA diagnostic criteria yields a very acceptable diagnostic accuracy rate of about 90%-95%. Nonetheless, the presence of a lab test with high accuracy would increase physician comfort with the diagnostic process and hopefully lead to a more proactive attitude toward early intervention.

My second reaction is rooted in 20 years of experience commercializing health care technologies. The discovery of a scientific means to diagnose a given condition is a very early step on the long and often arduous path to making a product available. This scientific advance is absolutely positive but the practical implications of the discovery are many years away from helping real patients.