Cognition Pharmaceuticals Reports its Lead Compound Statistically Significantly Improves Memory in Ills

Cognition Pharmaceuticals LLC of New York has reported very compelling results of a Phase II trial that demonstrated statistically significant results in a population of patients with cognitive decline associated with Multiple Sclerosis. The results are interesting on many levels. The trial failed to meet its primary end-points that were supposed to measure a drug effect on executive function but its secondary end-points that measured the drug’s effect on memory were significant. It seems Cognition may have had a case of asking the wrong question, but getting a better answer than they either hope for or expected. Cognition, it is time to change the hypothesis.

I tend to cast a jaundiced eye to trials with mixed results; however, the provenance of this agent is extraordinary. Its developers include Mark Bear, the Picower Professor of Neuroscience at MIT (the blog covered his pioneering work in identifying a path to curing Fragile X), Nobel Laureate, Leon Cooper and Neurosurgeon, Mel Epstein. This team represents the smartest kids in the class. The original theory of the compound’s mechanism of action was it would improve memory consolidation. This trial clearly illustrates that type of activity. The trial also confirms results from the compound's results animal models. The former CEO of the Sention, the company that originally developed the compound, commented in a recent book Can't Remember What I Forgot: The Good News from the Front Lines of Memory Research by Sue Halpern, that it, “…shot for the moon and missed.” In fact, Sention was probably on the mark and the compound was simply abandoned before broadly targeted trials were executed (Ms. Halpern, it is time to update your book before its next printing).

Central Nervous System (CNS) drug development is the Vietnam of the pharmaceutical industry. In the last year we have seen compounds from Myriad Genetics, Lexicon, Targacept (multiple indications), Memory Pharmaceuticals (multiple compounds and multiple indications), Nurochem, and Elan, all failed to meet primary end-points and almost all these compounds showed no signal in ills. Thankfully the C105 trial seems to have been well designed and executed. In a rare circumstance, a drug company maintained a mindset driven by science instead of marketing. This trial clearly demonstrates C105 is an active compound. Furthermore, the compound mechanism of action would argue a wide use across a wide variety of indications including but not limited to chemobrain, mild-Cognitive Impairment, cognitive impairment associated with Parkinson’s disease, cognitive impairment associated with Multiple Sclerosis, traumatic brain injury, and Cognition believes childhood learning disabilities.

Given that C105 is a member of the widely used amphetamine family, the development risk for this compound should be limited. Given its safety profile is good, it could be broadly prescribed. Given the dearth of compounds available to treat cognitive conditions, neurologists and psychiatrists are largely confined to offering off-label scripts that have little if any effect on memory improvement such as modafinil (fatigue), anti-depressants and ADHD drugs (attention); this agent demands to be put into multiple trials across a range of illnesses as the patient community not only will desire it but they deserve it. This drug may address a range of underserved illnesses for patients with unmet needs. Time is of the essence.

I will follow-up on this trial once more information is available.

MILITARY PERSONNEL WITH TRAUMATIC BRAIN INJURY AT RISK FOR SERIOUS LONG-TERM

The Institute of Medicine reported this week Military personnel who suffer severe or moderate traumatic brain injury (TBI) face an increased risk for developing several long-term health problems. This evidenced based study reported that conditions include Alzheimer's-like dementia, aggression, memory loss, depression, and symptoms similar to those of Parkinson's disease. Even mild TBI is associated with some of these adverse consequences, noted the committee that wrote the report.

In addition, the report notes that brain injuries sustained as a result of exposure to the force of an explosion without a direct strike to the head -- one of the most common perils for soldiers in Iraq and Afghanistan -- may be underdiagnosed due to the lack of research on blast injury. It calls for the U.S. Department of Defense and the U.S. Department of Veterans Affairs to step up clinical and animal studies of blast-induced neurotrauma (BINT).

The Healing Project would go further and immediately screen and database the 300,000 to 400,000 service members exposed to blasts.

"Explosive devices and other weaponry have become more powerful and devastating throughout the wars in Iraq and Afghanistan, and we are seeing much higher rates of nonpenetrating traumatic brain injury and blast-induced injury among military personnel who have served in these countries than in earlier wars," said George W. Rutherford, professor of epidemiology and preventive medicine and vice chair, department of epidemiology and biostatistics, School of Medicine, University of California, San Francisco, and chair of the committee that wrote the report. "It is important to identify and understand any long-term health effects of these injuries so that wounded service members do not lose valuable time for therapy and rehabilitation."

Studies conducted in Iraq by the Air Force Medical Service with the Headminder system would argue that up to 5% of exposures, that is 15,000 to 20,000 m-TBI injuries, would require additional follow-up. The DoD is only reporting 5,500 injuries total traumatic brain injuries. Furthermore, while animal studies are useful, replicating injuries in animals models are unlikely to provide necessary data to provide human clinical guidance. It is time to implement a web-centric longitudinal screening technology to track the evolution of these injuries in an epidemiologically sound fashion.

While we agree with the Institute in broad strokes, scientists and clinicians have been aware of the injuries and the likely outcome of these injuries since 2004. Neither the DoD or the VA has demonstrated any real interest in identifying or treating M-TBI dealing with its attendant co-morbidities. Both organizations have used research to delay the identification of and/or deny the very existence of the injuries. The report makes it clear blast concussion is not like a sports injury nor is it PTSD (two of the DoDs and VAs favorite excuses why they do nothing). Now that we have a change of government, it is time for Secretary of Defense Gates to clean out DoD HA and US Army Medcom. The delayers, the deniers and the dinosaurs need to be quickly cashiered and replaced by people who will get the job done now.

Lifestyle Affects the Development of Alzheimer’s

Two studies presented at the American Academy of Neurology meeting pointed to link between smoking drinking and cholesterol levels and the development of Alzheimer’s Disease (AD).

In a study of 900 people over 60 conducted by Mt Sinai Hospital (New York) found people who had more than 2 drinks a day and those who smoked more than a pack of cigarettes coupled with have the ApOE4 gene variant developed AD on accelerated basis. Smokers developed AD two years earlier than expected and drinkers five years earlier than expected. If you were both a heavy smoker and heavy drinker with the ApOE4 expression you would develop AD 8.5 years earlier than expected.

If one wish to delay the onset of AD stop smoking and curtail your consumption of alcohol.

A second study tracked 9,700 men and women from age 40 tracking the level of cholesterol and the rate of development of AD. It found that individual in the high cholesterol group were 1 and ½ times more likely to develop AD than the low cholesterol group.

If you wish to reduce your chances of developing dementia, eat a balanced diet, exercise, control your cholesterol and watch your weight.

These studies affirm that are genetics are not the sole determinant of outcome and that we can adjust our lifestyles to delay the onset of dementia.

Lipitor Fails to Demonstrate a Positive Effect as an Adjunctive Therapy with Aricept

The LEADe study was 18 months in duration and included 640 patients. The patients presented with mild-to-moderate Alzheimer’s disease (AD), the addition of Lipitor (atorvastatin calcium tablets) 80 mg to Aricept® (donepezil HCl) 10 mg showed no significant differences in cognition or global function (key measures of Alzheimer’s progression) compared to placebo plus Aricept 10 mg. No statistically significant results were demonstrated on secondary end-points that included cognitive, behavioral and functional measures.

A more interesting study would be to investigate the statin families prophylactic efficacy on a broad range of dementias. It is reasonably to hypothesize that statins may have a positive effect on a range of dementia by reducing the stress on the coronary system and/or reducing inflammation.

Alzheimer’s Target Finally Questioned

The Washington Post published an excellent article, Alzheimers Research Target May Be a Dead End

For nearly 20 years the Beta Amyloid Theory of Alzheimer’s disease has been pursued to the exclusion of a number of other promising disease theories. Chemistry seems to have trumped the near religious zealotry that has delayed finding treatments and a cure for the disease. A study published in the Journal Nature Chemical Biology by a team of chemists at the University of California, San Francisco, found that these candidate drugs form large, unwieldy clumps themselves, rendering them useless as targeted therapy against amyloid in the brain. The author’s suggestion to neuroscientists investigating these agents as potential Alzheimer's therapies: "They should stop."

Perhaps the community can also stop wasting time on PET scanning.

Nothing is wrong with science failing; it is expected. What is wrong, is scientists blithely denying facts demonstrated by clinical experience.

It is time to play catch-up and really find out how to deal not only with Alzheimer’s but also dementia.

Reversal Of Alzheimer's Symptoms Within Minutes In Human Study

The ScienceDaily reported on January 9th an extraordinary new scientific study, which for the first time documents marked improvement in Alzheimer’s disease within minutes of administration of a therapeutic molecule. The article referenced has been published in the Journal of Neuroinflammation.

The new study, entitled “Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration,” and the accompanying commentary, entitled “Perispinal etanercept: Potential as an Alzheimer’s therapeutic,” are available on the Web site of the Journal of Neuroinflammation.

The case study highlighted is a single patient in a 15 subject non-placebo controlled off-label study of the Etanercept (Enbrel). Etanercept is a tumor necrosis factor-alpha (TNF) Antagonist, that is, it blocks the activity of TNF. The agent is a FDA approved for the treatment of various forms of arthritis. Etanercept was administered to the spine under the hypothesis that elevated levels of TNF interferes with neural transmissions in the brain.

Following administration of Enbrel in the subject, his cognitive faculties demonstrated marked improvement within minutes.

The Healing Project consulted with leading experts in drug development and Alzheimer’s disease who have reviewed the article. While only a single case, the methods and measures used on the subject paint a compelling case that a double-blind placebo controlled trial should be undertaken with sufficient power to answer the question whether Enbrel administered through the spine can produce similar results in a large population. Our experts caution, that factors regarding this patient (general health, lack of overlapping morbidities, large cognitive reserve etc.), would limit the likelihood that all patients in a larger trial could achieve a similar result. Further, the effect demonstrated in this patient was not likely to be disease modifying but a result of increased brain efficiency due to the relief of neural inflammation. In addition, the nature of Enbrel would limit its use across the broadest possible population. Finally, no inference can be made regarding Enbrel’s disease modifying properties without a carefully designed trial to answer that question.

A small number of experts have already chimed in dismissing the Alzheimer’s inflammation hypothesis. The dismissal is based upon studies that failed to demonstrate efficacy using NSAIDs. (This would further imply all drug development in dementia should be terminated based on all current theories of the disease. No compound has demonstrated efficacy or ecological validity.) There are numerous reasons why these agents failed to demonstrate efficacy and bear no relationship to TNF Antagonists. Keep in mind, many of these experts are conflicted due to their support of alternate theories of disease treatment, disease diagnosis and disease process. The attempt to summarily dismiss these results confirms why the progress in dementia research has been retarded for two decades.

It is essential that every reasonable avenue research be pursued to relieve Alzheimer's symptoms and hopefully identify a cure. Given our belief, that dementia better characterizes the loss of memory in aging, Enbrel, if proved efficacious, would be an element of a complex treatment protocol that would benefit a large subset of patients along the arc of the illness.

November is Alzheimer's Awareness Month

The Healing Project wishes to take this opportunity to cast a light across the entire spectrum of dementia. Alzheimer’s is a term often used as a catch-all for a group of symptoms characterized by a loss of memory judgment, language, motor skills, and impairment of other cognitive skills due to the damage or death of neurons. Alzheimer’s is large subset of dementia, but Alzheimer’s patients often present with more than one dementia. Complicating matters, many Alzheimer’s patients also exhibit depression, severe mental illness and other psychiatric conditions.

Diagnosis and Misdiagnosis
In the hands of a skilled clinical team, the diagnosis of Alzheimer’s can approach 85% in accuracy. Community-based screening techniques being pioneered by Rhonna Shatz, MD of the Henry Ford Health System offer the best model not only for correctly identifying patients’ disorders but also offering families the best continuity of care for those afflicted with dementia. It combines the latest technologies, medical instruments and clinical methods to render an accurate diagnosis and treatment.

It is essential that patients’ presenting with severe memory impairment are carefully and professionally screened for nutritional deficiencies (B1, B12, Folate), metabolic disorders (thyroid,etc.) depression, psychiatric illness, negative drug synergies (pharmaceutical dementia) before any formal diagnosis is made. All of the above conditions can be treated and the cognitive decline in many cases reversed. If none of the above conditions are present, a baseline genetic and medical history should be compiled to determine the probable type of dementia the patient might have. A panel should be assembled review the patient's case history that should include a cardiologist, neurologist, neuropsychologist, gerontologist and a psychiatrist. After the determination is made, the gerontologist or neurologist should design a course of care for the patient and the family should be counseled on caregiving practices and social services that may ease the transition as the ailment progresses.

Regrettably, the training of general practitioners has been lacking and many still use such flawed instruments such as Mini-Mental Status Exam (MMSE) to make a diagnosis. At the early stages of the dementia, the MMSE is a useless instrument and at late stages it is not very relevant as a child could identify the impairment. Newer, more powerful, cognitive screening instruments, such as the Headminder Cognitive Screening Tool (CST), are available but low reimbursement rates make its use limited only to the most advanced medical centers. Since no cure is available for Alzheimer's or any organic form of dementia and the available treatments are of limited value, little emphasis is placed on the screening and diagnosis of dementia in family practice.

Why Is Early Diagnosis Important?

Early diagnosis is important for two reasons:

1. Identifying patients early allows families to develop the resources and build the a support system necessary to comfort the afflicted; and
2. Identifying patients early offers the opportunity to participate in clinical research trials essential to the development of new courses of treatment for dementia.

For information about ongoing clinical trials visit Clintrials.gov. The Healing Project can not emphasize enough that every available patient should volunteer for these trials as it is the only hope of finding useful drugs.

Current Drugs

The leading drugs available are the cholinesterase inhibitors such as Aricept and for later stage cases Namenda. Neither Aricept nor Namenda reverse the course of Alzheimer’s disease and have limited efficacy in treating the symptoms of Alzheimer's. Neither drug alters the progression of the disease.

Future Development

More than 60 drugs are in clinic, but it is highly unlikely any compound will make it to approval. It is not that some of these compounds lack efficacy, it is manner in which they are screened and tested. The FDA and EMEA (Europe’s FDA equivalent), must re-examine how the drugs are tested to ensure those that do work are properly identified. The second issue is Alzheimer's research has been largely focused on a single theory for more than 20 years. The theory may simply be targeting a symptom as opposed to the cause or causes of Alzheimer’s. Precious time has been lost and a vast amount of resources misallocated. Clinical experience and post-mortem analysis argues that the etiology of the disease and its complex co-morbidities demand a radical rethinking of the conduct of Alzheimer’s research. The Alzheimer’s patient community must demand that both the NIH and Alzheimer’s research community begin to fund alternate theories of the disease process.

What can be done now?

If a loved one is exhibiting symptoms associated with dementia, it is incumbent on the family to seek the best diagnostic center available in their area. In the event the patient is diagnosed with dementia or Alzheimer’s, families should take full advantage of all the services available to help care for the afflicted. Proper nutrition, exercise and human interaction can have positive results in mitigating the speed of cognitive decline in most patients.

The Healing Project has published Voices of Alzheimer’s to offer perspective patients, caregivers, and families dealing with Alzheimer’s. It is available for purchase from Amazon.

Resources can be found at The Healing Project’s links section select Alzheimer’s.









For more information regarding Alzheimer’s Awareness Month’s activities:

National Alzheimer's Disease Awareness Month
Alzheimer's Association
225 North Michigan Avenue, 17th Floor
Chicago, IL 60601-7633
(800) 272-3900
(866) 699-1246
info@alz.org
http://www.alz.org/