Did Pfizer "Hide" a Potential Treatment for Alzheimer's Disease?

Contributed by: Dennis Fortier, President, Medical Care Corporation _______________________________________________
Despite the provocative title, this post is largely a summary of a non-story. However, it is worth discussing because this "non-story" has been widely covered in the general media, often in a manner that leans strongly toward the sensational end of the news spectrum.

The facts are fairly non-controversial. Pfizer, a major pharmaceutical drug developer and marketer, performed an analysis of medical insurance data comprised of approximately 254,000 patients with rheumatoid arthritis or another inflammatory disease. The analysis revealed that, among those patients whose inflammatory disease was being treated with Enbrel, a drug marketed by Pfizer in the US, a slightly smaller percentage also had an Alzheimer's diagnosis compared to those who were not treated with Enbrel. Despite the seeming potential for Enbrel to prevent Alzheiemr's disease, Pfizer conducted further internal review and opted not to initiate a clinical trial for the purpose of measuring the efficacy of Enbrel in preventing Alzheimer's disease.

As far as I can tell, no one is disputing those facts. However, how those facts are interpreted has become a matter of creative reporting. One angle that has created a fair amount of reporting (initially in the Washington Post) suggests that, because Enbrel is nearly off patent, after which the drug will be far less profitable, Pfizer made a greedy decision and opted not to pursue a potentially promising Alzheimer's treatment. Most drug development experts disagree with that suggestion.

The noted statistical evidence of a preventative effect of Enbrel against Alzheimer's disease was far smaller than what the drug development industry would generally require before initiating a trial. Furthermore, the effects of anti-inflammatory drugs in the Alzheimer's space have been thoroughly investigated in other studies to no avail. Given that Enbrel does not cross the blood-brain barrier, it is fairly unlikely that a long and expensive trial (see previous summary here of FDA drug approval process) would yield a favorable outcome. In fact, another major marketer of pharmaceutical drugs (Amgen), who holds the rights to Enbrel outside of the US,  reviewed the same data and also concluded that further investigation was not warranted.

Overall, small statistical patterns are commonly present in large data sets like the one discussed here. However, such patterns are not necessarily indicative of an underlying treatment with a clinically meaningful effect. In the opinion of most knowledgeable scientists (as summarized here by Derek Lowe), Pfizer made a prudent decision not to further evaluate Enbrel as a potential treatment for Alzheimer's disease.

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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. ____________________________________________________________

Optimism About New Alzheimer's Drugs

Contributed by: Dennis Fortier, President, Medical Care Corporation

A few weeks ago, we wrote about the glimmering ray of hope that had emanated from bad news about potential new Alzheimer's treatments.

Both Bapineuzumab and Solanezumab, the two most progressed new drugs in the development pipeline, had both failed the final stage of their respective clinical trials, and would not be approved by the FDA. However, there was some evidence, and much speculation, that both drugs had shown signs of efficacy in secondary data analyses.

Now, as presented at the American Neurological Association's 2012 annual meeting earlier this week, those secondary analyses have been verified and a newfound optimism has swept the field.

Of course, drug approvals require a massive investment of time and money, and drug companies must always weigh the costs of completing that high risk process, against the benefits they might capture during the few remaining years of the drug's patent life, once the process is completed and the drug is commercialized.

Readers might be surprised to learn that drug companies sometimes abandon effective drugs, if the approval process takes too long and the viable (patent protected) period for recouping their investment is too short. This is the decision that Eli Lilly (Solanezumab) and Pfizer (Bapineuzumab) must now face as they consider the time and cost of next steps to bring these drugs to market.

At this point, there are two encouraging signs that each company might push forward and lobby the FDA for an efficient path to near-term approval.  One is that the Federal government, under the National Alzheimer's Prevention Act, is committed to identifying new treatments for this disease.  The other, is that the Wall Street analysts, ever pessimistic about success of new AD drugs, have pushed Lilly's stock price upwards in the wake of this new information.

The End of Dimebon

Contributed by: Dennis Fortier, President, Medical Care Corporation

Dimebon, an experimental Alzheimer's treatment, has failed its Phase III clinical trial, and will not be further developed by its co-sponsors, Pfizer and Medivation.

The Associated Press article reporting on this failure described it as a "major setback" but it really comes as no surprise to those who have followed the trajectory of this potential new drug.

As we described in an earlier post, Dimebon failed its initial trial showing no cognitive benefits and no improvement of function among those research subjects who took it.  Undaunted by the initial failure, the drug's sponsors pushed forward with three additional trials: one measuring the drug's effect over a longer period, one measuring the drug's effect as poly-therapy in conjunction with Aricept, and one measuring the drug's effect in patients with Huntington's disease.  All three trials have now failed.

This is not good news for the field but I think it important to comment on how this might effect attitudes toward further research.  By and large, even the first Dimebon failure in March of 2010 was expected by most experts who follow this space.  Despite the fact that Pfizer and Medivation chose to push forward and complete three additional studies, consensus was that the drug was unlikely to be effective, and success in those trials was considered an absolute long-shot.

Now, those expectations have been met, and no one is really surprised.  Research will continue at a cautious but steady pace, perpetually fueled by the lucrative potential of success.

Controversy over High Dose Aricept

Contributed by: Dennis Fortier, President, Medical Care Corporation

 A consumer advocate group is calling for a ban on the 23mg Aricept dosage, which was approved by the FDA for more severe stages of Alzheimer's.

While Aricept is the mostly widely prescribed drug for the treatment of AD, it is most commonly prescribed in 5mg and 10mg doses.  Its efficacy in controlling symptoms is only moderate, but it has been on the market for more than a decade and has a solid safety profile.  The more recently approved, higher dosage of 23mg has been associated with a higher incidence of side effects and, according to the advocacy group Public Citizen, has no greater efficacy.  The primary side effects are nausea, vomiting, and agitation.

It is unclear whether the FDA will act on the petition to review the data and reverse the former approval for this dosage.  However, the most salient point for treating physicians to understand is that, regardless of the dosage, cholinesterase inhibitors like Aricept yield the most clinical benefit when prescribed as poly-therapy along with Namenda.  The data supporting this clinical approach are clear and compelling.

Bapineuzumab: Speculation on Alzheimer's Drug

Contributed by: Dennis Fortier, President, Medical Care Corporation

Bapineuzumab is an Alzheimer's drug that is now in the final stage of FDA approval. We described the mechanism of Bapineuzumab in this earlier post.

No one can say with any degree of certainty if it will be approved or not, but as noted in an update provided by Fierce Biotech,  there has been an interesting development in the progress of the clinical trial.  The companies sponsoring the trial, Pfizer/Wyeth and J&J, amended the protocol last year to expand the study by several thousand research subjects.  This is a very costly move in terms of research investment and time required to conclude the study, and has led to much speculation as to why the trial was expanded.

A leading theory that makes lots of sense, is tied to the recently revised guidelines for diagnosing Alzheimer's disease.  Under the new guidelines, the presence of disease pathology can be recognized much earlier, when symptoms are much subtler, compared to the former standards.  This bodes well for more effective treatment.

However, the new guidelines also create a potential conundrum in terms of currently approved treatments.

The FDA has approved 4 drugs for treating Alzheimer's, but all of those approvals are based on the former definition of the disease, that requires a later stage of disease progression and more severe symptoms before the diagnosis can be made.  It is possible that the Bapineuzumab trial was initiated to demonstrate efficacy against the late stage disease that was defined in the old guidelines, but revised to demonstrate efficacy against an earlier stage of disease as defined in the revised guidelines.

Although the trial protocol was amended about a year before the new guidelines were released, a draft version of the revisions have been available and mounting industry consensus has been visible for quite some time.

If the drug works, and the trial sponsors can demonstrate that it works at very early stages of Alzheimer's, this could be a giant leap forward for the field.

Dimebon Fails Phase III Trial

Contributed by: Dennis Fortier, President, Medical Care Corporation
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The best candidate for a new Alzheimer's treatment has taken a step backwards with the failure of Dimebon to show a benefit in the CONNECTION study. While it is not surprising for a drug to fail a trial, especially in the Alzheimer's space where the disease is poorly understood, there was a sense of optimism around Dimebon that I hadn't sensed in some of the other recent trials.

In this study, 598 adults with mild to moderate AD were given either Dimebon or a placebo for a six-month period and effect on cognitive function was evaluated. Unfortunately, the drug group did not out-perform the placebo group.

The drug sponsors (Pfizer and Medivation) are conducting other trials for Dimebon including one in later stage patients and another in conjunction with Aricept. There is some hope that the drug could be approved with narrower indications based on success in one of these other studies.

Nonetheless, this result was a disappointment and bodes poorly for the immediate future of AD treatment.

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.

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.

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.