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Pfizer, Medivation end development of potential Alzheimer’s treatment Dimebon

admin — Sat, 21 Jan 2012 12:26:49 +0000

TRENTON, N.J. — In a major setback for patients and doctors, drugmakers Pfizer Inc. and Medivation Inc. have halted development of a potential Alzheimer’s disease treatment after the drug for a second time yielded disappointing results in a late-stage clinical study.Dimebon was furthest along in testing among the experimental Alzheimer’s drugs being developed to try to stop or even reverse the course of the mind-robbing disease. Dimebon would have been the first such drug and specialists just a couple of years ago had hoped it would be on the market this year.

Pfizer, the world’s largest drugmaker by revenue, and Medivation said on Tuesday that Dimebon failed to significantly improve cognitive ability, as well as self-care and daily functions in patients with mild-to-moderate cases of the disease. The study involved about 1,000 patients who had Dimebon added to their ongoing treatment with Pfizer’s former blockbuster Alzheimer’s drug donepezil, or Aricept.

Aricept, jointly marketed by Pfizer and Japan’s Esai Co. Ltd. and once heavily advertised, had about $3.7 billion in sales in 2009. It lost U.S. patent protection in November 2010, and sales have since plunged.

Dimebon, known chemically as latrepirdine, would have been an even bigger blockbuster if it had panned out. The experimental drug looked promising after it kept Alzheimer’s symptoms from worsening for a year in an earlier patient study.

But Dimebon didn’t work as hoped in a late-stage trial in which patients took it for six months. After those results, announced in March 2010, the companies said they were continuing three other studies that could prove Dimebon helped patients in combination with other Alzheimer’s drugs or when used for a longer period.

Then last April Pfizer and Medivation said Dimebon also failed in another late-stage clinical trial, when it did not improve symptoms of the neurologic disorder Huntington’s Disease.

After the latest failure, New York-based Pfizer and Medivation, headquartered in San Francisco, said they are ending development of Dimebon, as well as their agreement to market the potential treatment.

Pfizer still has one Alzheimer’s treatment in late-stage testing, bapineuzamab, which it is jointly developing with Johnson & Johnson. It’s a biologic drug, grown in living cells rather than made by mixing chemicals, and works differently than Dimebon.

Alzheimer’s disease is the most common form of dementia, and drugmakers are trying to find a treatment that does more than temporarily ease the symptoms: memory problems, confusion, aggression and a general decline in ability to function, which together can hasten death. Many drugs have flopped in late-stage testing in recent years, including some that seemed to clear harmful plaque from afflicted brains.

The newest drug for Alzheimer’s symptoms, Namenda, was approved back in 2003.

Cases of Alzheimer’s disease are expected to triple by 2050, to around 106 million people worldwide. The disease strikes nearly a half million new patients a year, mainly as people hit their 70s or 80s.

In trading Tuesday, Pfizer shares rose 9 cents to $21.93, while Medivation stock dropped $1.82, or 3.3 percent, to $53.90.

http://www.washingtonpost.com/business/industries/pfizer-medivation-end-development-of-potential-alzheimers-treatment-dimebon/2012/01/17/gIQA91uF5P_story.html

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Clinical Trial Results Could Promote the Use of Dimebon Throughout the Course of Alzheimer’s Disease, According to New Findings from Decision Resources

admin — Tue, 06 Dec 2011 06:28:08 +0000

Decision Resources, one of the world’s leading research and advisory firms for pharmaceutical and healthcare issues, finds that, if Pfizer/Medivation’s Dimebon shows efficacy in two ongoing clinical trials in moderate to severe Alzheimer’s disease that is equivalent to the impressive clinical trial data it has already shown to date in mild to moderate patients, these positive data would promote the use of Dimebon throughout the course of the disease. As a result, following its expected launch in 2012, Dimebon will garner peak year sales of $1.5 billion in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.

The Phase III CONTACT clinical trial for patients with moderate-to-severe Alzheimer’s disease will investigate the effect of Dimebon on neuropsychiatric symptoms and activities of daily living in patients who are already receiving a stable dose of donepezil (Eisai/Pfizer’s Aricept, Bracco’s Memac). The Phase III CONSTELLATION clinical trial will investigate slightly different end points: the effect of Dimebon on cognition, memory and activities of daily living in patients already receiving a stable dose of memantine (Merz/Grupo Grunenthal’s Axura/Akatinol, Lundbeck’s Ebixa, Forest Laboratories’ Namenda).

The Pharmacor finding from the topic entitled Alzheimer’s Disease also reveals that, through 2018, robust 11 percent annual growth in the Alzheimer’s disease drug market will be driven by the launch and uptake of new anti-amyloid monoclonal antibodies, most notably Johnson & Johnson/Pfizer’s bapineuzumab and Eli Lilly’s solanezumab.

“Although monoclonal antibodies are expected to offer superior efficacy over other drugs in the market, their uptake will be initially slow following their launches, owing to potential safety concerns,” said Decision Resources Analyst Matthew Winton, Ph.D. “Nevertheless, bapineuzumab and solanezumab will achieve combined sales of nearly $6 billion in 2018.”

About Pharmacor

The newly redesigned Pharmacor advisory service offers clients in the biopharmaceutical industry the most up-to-date information available on commercially significant disease topics.

About Decision Resources

Decision Resources ( www.decisionresources.com ) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.

About Decision Resources, Inc.

Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions.

All company, brand, or product names contained in this document may be trademarks or

registered trademarks of their respective holders.

http://www.prnewswire.com/news-releases/for-the-treatment-of-alzheimers-disease-pfizermedivations-dimebon-will-garner-peak-year-sales-of-15-billion-81128002.html

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Pfizer throwing money to buy 700 million experimental drug Dimebon-Pfizer, drug, Dimebon-pharmaceutical industries

admin — Thu, 20 Oct 2011 09:04:26 +0000

Recently, Pfizer agreed to pay San Francisco-based Medivation Inc. up to 725 million U.S. dollars of funds to be used to treat other developed experimental Alzheimer’s drug Dimebon. This is the world’s largest pharmaceutical companies in deals this year, the ninth operation. Under the agreement, Medivation will receive Pfizer USD 225 million down payment, as well as drug listing process, linked to up to 5 million milestone payment.

Hot Present, pharmaceutical companies are racing to develop for the treatment of Alzheimer’s disease drug. Analysts believe that 2012, the size of this market could grow to 20 billion U.S. dollars. Although Pfizer has been on sale for Alzheimer’s disease therapy Aricept, but in 2010, the drug will face competition from generic drug companies, while the other is developing Alzheimer’s Treatment drugs have not yet entered the final testing stage. Therefore, the transaction may help Pfizer in the treatment of Alzheimer’s disease to achieve a quantum leap in the field, and with the development of such drugs, Lilly, Wyeth and Elan Corporation to compete.

Pfizer has the world’s best-selling drug Lipitor last year, this reduction Cholesterol Drug sales 12.7 billion. However, Lipitor will lose patent protection in 2011 and faces generic competition this end, the hands hold 29,000,000,000 US dollars cash, Pfizer is searching for new drugs to cover sales of Lipitor left empty .

Analyst at Miller Tabak in New York LesFuntleyder that, although Alzheimer’s disease is a difficult to treat disease, but Pfizer, this deal appears to be a positive risk-return opportunities, if Pfizer wants to make up for the next few years will experience significant economic losses, it needs to continue aggressive.

Two companies will share development and marketing in the United States, of which 60% of the cost of Pfizer’s commitment to share in the United States to achieve 60% profit. Pfizer will be responsible for sales outside the United States Dimebon, Medivation Inc. to pay the sales commission. In order to be allowed in the U.S. market, Medivation and Pfizer Inc. are jointly carrying out the work of the last test in order to make good to the U.S. regulatory approval for preparation.

High hopes Medivation Inc. was founded in 2003, currently has 40 employees. In the second quarter, Medivation losses amounted to 18.5 million U.S. dollars, compared with last year’s 7.2 million U.S. dollars increased substantially. Medivation’s Dimebon is the main product. 80s of last century, it first as an antihistamine in Russia. To the 90?s, the Russian chemist SergeyBachurin in a variety of laboratory animal tests showed that the drug has the potential to improve the animal’s cognitive abilities. But in the United States, almost no attention to these findings, until the bio-technology entrepreneurs DavidHung discovered in 2003, these studies, the situation began to change. DavidHung visit to Russia in the field heard the results, he decided to set Medivation Inc., began commercial operation of the drug.

Pennsylvania RaymondMyers Emerging Growth Equities analyst, said Pfizer is a great Cooperation Partners, it has tremendous marketing tentacles, especially in the areas of primary health care; Pfizer With Aricept Alzheimer’s disease treatment in a leading position in the field.

According to the British medical journal “Lancet” published in July a study, Dimebon may help Alzheimer’s patients remember the date, understand medication instructions, follow commands, memorize some words and perform simple activities.

http://focusincholesterol.com/pfizer-throwing-money-to-buy-700-million-experimental-drug-dimebon-pfizer-drug-dimebon-pharmaceutical-industries

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Pfizer/Medivation Dimebon fails as Huntington disease drug

admin — Tue, 02 Aug 2011 14:38:32 +0000

Pfizer and Medivation’s Dimebon, which failed as a potential treatment for Alzheimer’s last year, has now disappointed in a late-stage trial for Huntington disease.

The companies have presented results from the 403-patient Phase III HORIZON study of Dimebon (latrepirdine) which show that the drug did not achieve statistical significance for either of the co-primary endpoints of the trial. Full results are expected to be presented at an upcoming medical meeting.

David Hung, Medivation’s chief executive, said “we are disappointed with the results of the HORIZON trial given the high unmet need in this patient population”. He added that “at this point, we will discontinue development of Dimebon in Huntington disease, including the ongoing open-label extension study”.

However this may not be the end of the road for Dimebon, which was first sold in Russia as an antihistamine. Dr Hung noted that the firms will continue a 12-month Phase III trial looking at the benefit of adding Dimebon to Eisai/Pfizer’s Aricept (donepezil) in patients with mild-to-moderate Alzheimer’s disease. Top-line data from that study is expected in the first half of 2012.

Last March, Dimebon failed in an Alzheimer’s trial where no statistically significant improvements were achieved on cognition, global function, activities of daily living or behaviour.

Pfizer linked up with Medivation in September 2008 in a deal which saw the latter pocket an upfront cash fee of $225 million with milestone payments of up to $500 million, depending on the success of Dimebon.

http://www.pharmatimes.com/article/11-04-12/Pfizer_Medivation_Dimebon_fails_as_Huntington_disease_drug.aspx

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Hungry for Breakfast? Dimebon is TOAST

admin — Fri, 29 Jul 2011 14:32:05 +0000

Okay, maybe not quite yet breakfast food for Alzheimer’s disease when added to Aricept (donepezil). But here’s my prediction: CONCERT will publish 1Q2012 and then we should officially be ready to butter dimebon (latrepirdine; Pfizer / Medivation) once and for all.

As for today’s news, results from the Phase 3 HORIZON trial: Dimebon (latrepirdine) in patients with Huntington disease, did not achieve statistical significance for either of the co-primary endpoints, the Mini-Mental State Examination (MMSE), which measures cognition (p=0.39), or the Clinician’s Interview-Based Impression of Change, plus caregiver input (CIBIC-plus), which measures global function (p=0.84). “We are disappointed with the results of the HORIZON trial given the high unmet need in this patient population. At this point, we will discontinue development of dimebon in Huntington disease, including the ongoing open-label extension study,” said David Hung, M.D., president and chief executive officer of Medivation. “We will continue our ongoing 12-month Phase 3 CONCERT trial of dimebon and its open-label extension in patients with mild-to-moderate Alzheimer’s disease. We expect to report top-line data from CONCERT in the first half of 2012.”

We believe that when CONCERT (donepezil +/- dimebolin) publishes it will be a negative study. As far as an approvable therapeutic for Alzheimer’s disease we think Dimebon is toast. The basis for this is the changing view of BOLT’s Alzheimer’s Disease Thought Leader panel from 2009 to 2010. In 2009, there was some level of interest in dimebon for AD, as the Russian data had just been published. But by 2010, as our panelists who were involved with the drug once it hit Western clinical sites, had an opportunity to look more closely, their enthusiasm waned. That’s not a good predictive marker! (and that was a pretty poorly constructed sentence. With writing skills like this I should probably stop blogging and get a day job with the Associated Press). Anyway… here are some of the comments from BOLT’s Alzheimer’s Disease Thought Leader panel:

“I have to say I would have put Dimebon on that list. Dimebon might be a good adjunct to donepezil and memantine yet, but I think Dimebon’s day has come and gone. From all the signals I am seeing I don’t know that it has a long-term survival. I am going to take Dimebon off my list”.

“We had Dimebon. I would have mentioned Dimebon but I am not mentioning Dimebon now because it seems to have not done well in the most recent study. Now it seems like they have just continued some of their studies. That has dropped way down now on the list”.

“Dimebon is an interesting story. It was a molecule looking for a mechanism of action, not the other way around and even the company back away from the acetyl cholinesterase inhibition and the NMD antagonists and said we have exciting mechanism of action but we are not sure what it is. They really are moving toward their mitochondrial activity, which would be really terrific if it occurred. I asked them point blank why aren’t you going after mitochondrial myopathies because Dimebon could be a good treatment for mitochondrial myopathies and it is simply business. They said, look, there is a very low market in mitochondrial myopathies and there is a huge market in Alzheimer’s. It still might work in Huntington’s but I am, again, a little cautious about Huntington’s. If the CONCERT study is negative then the drug is dead. Period. And that will publish when? I think they could announce CONCERT data by the summer. The study is done in terms of enrollment. CONCERT was a donepezil adjunct. A lot of people worry on the basis that the CONCERT and CONNECTION is that their treatment periods are short, only six months. I think we are banking on the Russian data to show them a signal. But I think the issue with CONNECTION was that the placebo group did not decline. That is why it was negative. It is more inconclusive than it is negative. That is not going to get Pfizer an indication. I agree”.

Dimebon is viewed as an important addition for patients whose disease has progressed beyond the point of reversibility, who need stabilization or a boost to their functional status. There is more uncertainty that the drug has a clinical effect related to its ability to stabilize mitochondria or affect NMDA.

“The Dimebon I found intriguing. That kind of falls into the same thing as analogous sirtuin-1. I don’t know how it is acting. That really intrigues me and easily could be important. So that seems useful. Why does it matter how it is working if it is working? It doesn’t. It just matters whether you believe it. Phase II trials sometimes even in the phase II sometimes look good and then fail, right. Right. Sure. So people would be just intellectually a little more confident if they knew how it was working but I totally agree with you. I don’t think it matters. Antidepressants, they didn’t know how they acted or antipsychotics for the longest time they didn’t know how they acted but they still were used. So I agree with you it doesn’t matter. And it is very intriguing and the mechanism appeals to me. I had even published something that is a mitochondrial protectant that also looks good so I like that approach. It is just a little bit different. So Dimebon is one that almost made it onto the list. I was debating, but without a mechanism, I just thought that might fail. But I certainly would really believe that it could be very useful”.

“So the landscape is always changing and in a very exciting kind of way. I will say to you right now that the drug that is at the top of the list of the fancy formulary despite the fact that I don’t think it is going to be as robust in the US data as in the Russian data I think the drug that is likely to emerge at the top of the list is Dimebon, strictly as a symptomatic drug. You can parse out all the mitochondrial data and NMDA data you like but at the end of the day I think it will be similar to a cholinesterase inhibitor in terms of its scope and magnitude of effect and will be part of the landscape sooner than later”.

“I think we can do better than what we are doing now. I am not sure whether that is going to be a 5HT drug or some unknown symptomatic mechanism, a Dimebon-like drug. I think we are going to do better than we are doing now. I think Dimebon is likely to succeed. I would probably put that in this category. I hope it is disease-modifying as well but I am certain it is symptomatic and looks better than what we have got. So I just put that on the list because I think we can do better for symptomatic treatments as well”.

“I don’t have anything against Dimebon. It is very attractive but without knowing its mechanism of action or without seeing more in the way of long-term clinical outcomes, it is hard for me to think that this is more than another symptomatic therapy. If it turns to that it is complimentary then that would be attractive. I think without some reason to think that it was really a disease-modifying therapy it would be hard to get too enthusiastic about just adding yet another symptomatic therapy to cholinesterase inhibitors and to Namenda. So that is why it didn’t make my list. Now I understand the evidence refutes the possibilities that this is a cholinesterase inhibitors or an NMDA antagonist. So I am comfortable it is not just another version of the existing therapies. But I don’t think there are any great evidences to what the actual mechanism of action is”.

“Then I would still like to have a symptomatic treatment. Is there anything that I would pick better than a cholinesterase inhibitor? I’m not sure if Dimebon really works? So the next one would be from the group of cholinesterase inhibitor or Dimebon or Memantine kinds of symptomatic treatment because I would not want to be limited to a formulary that didn’t have that safety net for the people that came to you late”.

http://www.boltinternational.com/2011/04/hungry-for-breakfast-dimebon-is-toast/

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Pfizer throwing money to buy 700 million experimental drug Dimebon-Pfizer, drug, Dimebon-pharmaceutical industries

admin — Tue, 19 Jul 2011 13:32:33 +0000

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Dimebon a No-Go for Huntington’s Disease

admin — Thu, 23 Jun 2011 13:03:39 +0000

Dimebon, the old Russian cold medicine that held promise as a treatment for Alzheimer’s and potentially other brain diseases, is looking more and more like a dud.

In a late-stage trial in 403 patients with Huntington’s disease, a genetic progressive brain disorder, the drug didn’t significantly improve cognition or global functioning, Pfizer and Medivation announced today. The full results will be presented later this year at a scientific conference.

“Huntington’s is a challenging disease area, and we are also disappointed with the HORIZON results,” Steve Romano, head of Pfizer’s Medicines Development Group, said in a statement.

Last year, the companies announced negative results in phase III trials in the treatment of Alzheimer’s as well. But, a 12-month, late-stage trial of Dimebon called CONCERT will continue, the companies said. That trial examines the benefit of adding Dimebon to donepezil (brand name: Aricept), approved for mild, moderate and severe Alzheimer’s.

Dimebon had been the focus of much industry excitement after a small study on Alzheimer’s patients conducted in Russia had shown the drug had some benefit, though many experts urged caution because of the many differences between the patient population in Russia and those in many Western countries. In 2008, Pfizer shelled out $225 million to Medivation to develop and co-market the drug.

The Huntington trial results are “disappointing but not unexpected,” P. Murali Doraiswamy, a professor at Duke University and an investigator on the CONCERT study, tells the Health Blog.

Doraiswamy, who also served in the past as an advisor to Pfizer and Medivation, says he thinks the Huntington’s results don’t bode well for the drug’s effectiveness in Alzheimer’s. “I think this is bad news both for the drug and their postulated mechanism of action.” He said the companies haven’t informed him of any changes to the trial with which he is involved.

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Alzheimer’s Panel Calls for Large-Scale Study to Find Disease Risk Targets

admin — Tue, 24 May 2011 00:49:01 +0000

More extensive, and expensive, studies that follow large groups of people over generations are needed to combat Alzheimer’s, researchers said today in a report that cited the lack of progress in slowing the disease.

There isn’t enough evidence to prove anything can be done to prevent or delay the malady, which is expected to grow threefold and strike 16 million Americans by 2050, the researchers wrote today in the Archives of Neurology.

The report documented findings of a panel charged with compiling evidence on Alzheimer’s risk factors and preventive measures. Researchers cited the Framingham Heart Study, started in 1948 and spanning three generations, as the kind of trial needed to pinpoint who gets Alzheimer’s and why. The Framingham study identified elevated cholesterol and blood pressure, as well as cigarette smoking, as contributors to heart disease.

“Maybe we are going to prove that indeed there are associations, but for that we need more studies of good quality,” Martha Daviglus, one of the report’s authors and a professor of preventive medicine at Northwestern University, said in a telephone interview.

While Forest Laboratories Inc. (FRX)’s Namenda, and Pfizer Inc. (PFE) and Eisai Co.’s Aricept address symptoms, there is no way to slow or cure a disease that affects about 5.4 million Americans, the report concluded.

The message of the report isn’t that nothing works to reduce Alzheimer’s risk, Daviglus said. Rather, it’s that we don’t yet know what will.

Risk Factors

“We need to start the studies earlier not only because of environmental and lifestyle factors,” Daviglus said. “We need to find what their baseline was, when the adults were healthy. It’s the only way to know what risk factors are associated with the disease.”

Such research is pricey, said Bill Thies, the chief medical and scientific officer for the Alzheimer’s Association, a Chicago-based advocacy group. The Framingham study cost about $120 million, he said. The Alzheimer’s Disease Neuroimaging Initiative, meant to define the progression of the disease through brain scans, blood tests and cerebral-spinal fluid will cost about $140 million, Thies said.

The current yearly federal budget for Alzheimer’s disease is “a little less than $500 million,” he said.

The report notes that some studies suggest physical activity reduces Alzheimer’s risk, as does a vegetable-rich diet, and controlling diabetes and blood pressure, Thies said.

“We know those are good things to do,” he said. “There’s no possibility that more physical activity does harm; there’s a net benefit and maybe it will also reduce the risk of Alzheimer’s disease.”

Clinical Trials

As of March 2011, there are six ongoing, late-stage clinical trials in Alzheimer’s disease, according to data from the Alzheimer’s Association. Those drugs include Baxter International Inc. (BAX)’s intravenous immunoglobulin; Pfizer and Johnson & Johnson (JNJ)’s bapineuzumab; Eli Lilly & Co. (LLY)’s solanezumab; Pfizer’s and Medivation Inc. (MDVN)’s Dimebon; a supplementary dose of resveratrol, the compound found in red wine; and a trail of Namenda in combination with vitamin E.

Also in today’s Archives of Neurology, researchers found that people who had a gene alteration associated with Alzheimer’s disease had fewer connections in certain parts of the brain. Those changes in brain structure suggest that alterations in connectivity may serve as an early biomarker for the disease.

A separate study found that two cerebrospinal fluid markers of Alzheimer’s disease did well at identifying people with Alzheimer’s pathology. However, the two tests identified different absolute values for the amount of Alzheimer’s-related proteins in the brain.

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Dimebon a No-Go for Huntington’s Disease

admin — Mon, 18 Apr 2011 14:34:18 +0000

Dimebon, the old Russian cold medicine that held promise as a treatment for Alzheimer’s and potentially other brain diseases, is looking more and more like a dud.

“Huntington’s is a challenging disease area, and we are also disappointed with the HORIZON results,” Steve Romano, head of Pfizer’s Medicines Development Group, said in a statement.

The Huntington trial results are “disappointing but not unexpected,” P. Murali Doraiswamy, a professor at Duke University and an investigator on the CONCERT study, tells the Health Blog.

http://blogs.wsj.com/health/2011/04/11/dimebon-a-no-go-for-huntingtons-disease/

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Tangles and plaques: unlocking the secrets of Alzheimer’s disease

admin — Fri, 18 Mar 2011 14:16:42 +0000

Despite many years of relentless research efforts, Alzheimer’s disease, the most common form of dementia, remains impossible to cure.

According to Alzheimer’s Disease International, 35.6 million people have the disease worldwide, but the number of sufferers is expected to triple by 2050. This will create a huge burden on unpaid carers and health and social care systems.

There are currently no drugs available that can stop or reverse the relentless march of Alzheimer’s disease. Of all the new therapies that have been investigated in the last ten years, more than 20 have failed late-stage clinical trials. But now, for the first time, three potential Alzheimer’s treatments are in phase III – so are we close to a breakthrough, or at least a step forward in fighting the disease?

Beyond cholinesterase inhibitors

Acetylcholinesterase inhibitors (AChEIs) are the current standard treatment, and help maintain levels of acetylcholine in the brain, which is essential to ensure the proper functioning of memory and cognition. They do so by preventing the breakdown of acetylcholine by the enzyme acethylcholinesterase.

There are three cholinesterase inhibitors on the market – Novartis’ Exelon (rivastigmine), Janssen and Shire’s Reminyl (galantamine) and Eisai and Pfizer’s market leader Aricept (donepezil).

The drugs can improve the symptoms, and delay the progression of Alzheimer’s disease, but they cannot halt or reverse its course.

The past few years have seen a surge of clinical trials of new Alzheimer’s drugs. These differ from existing treatments, as they target the likely cause of Alzheimer’s, rather than its symptoms. Researchers noticed that the brains of Alzheimer’s sufferers were distinguished by two distinct features – ‘plaques’ and ‘tangles’ in certain parts of the brain. It emerged that the plaques are deposits of the protein beta-amyloid (A?) that form outside nerve cells. The tangles are thread-like structures of the protein tau and form inside nerve cells. Most of the work in the last 20 years has centred around understanding the role of these two phenomena in causing the disease, in the assumption that they play a direct role.

The ‘Amyloid Hypothesis’ was first put forward in 1991, suggesting that Alzheimer’s disease is triggered by its action, and numerous drugs have sought to halt this process by increasing the removal of excess beta-amyloid from the brain, by reducing the protein’s production, or by preventing it from clumping into plaques.

Late-stage failures

Many drugs which have been designed to target beta amyloid have failed. Lilly’s semagacestat is one of the latest – the company announced it would end its clinical development in August 2010, following results from two phase III trials on patients with mild or moderate AD.

To the dismay of researchers, the trial showed that semagacestat actually accelerated the progression of the disease instead of slowing it down. The drug also led to a significant decline in physical and mental functioning, and increased the risk of skin cancer.

Semagacestat belongs to a class of drugs called gamma secretase inhibitors, which block the enzyme involved in the production of beta-amyloid molecules from its larger precursor protein, known as APP (amyloid precursor protein).

In 2008, another gamma secretase inhibitor, Myriad Genetics’ tarenflurbil was found ineffective at improving both the cognitive function and the ability to perform simple activities of daily living, such as dressing and eating, in patients with mild Alzheimer’s disease.

Similarly disappointing results had been obtained previously for Neurochem’s Alzhemed (tramiprosate). Alzhemed has yet another mechanism of action, binding to beta-amyloid molecules and thereby stopping them from clumping together into plaques.

These failures have cast doubt on the amyloid hypothesis, as there is no conclusive evidence that accumulation of beta-amyloid in the brain is the primary cause of Alzheimer’s disease.

Few doubt that beta-amyloid is somehow tied up with Alzheimer’s, but it is now clear the pathology is far more complex than first hoped.

According to Steven Paul, former head of Science and Technology at Lilly and president of Lilly Research Laboratories, the amyloid hypothesis isn’t wrong, but rather the new agents are being tested on the wrong patients.

Most phase III trials involve patients with mild or moderate AD. Paul says, the brain is too damaged to be rescued by anti-beta-amyloid drugs by this stage. For this reason, trials should involve patients earlier in the course of the disease.

Writing in the journal Nature, Paul points out: “It’s now clear that A? is building up and depositing in the brain a full decade or more before you even get mild cognitive impairment, which is considered to be the prodromal state of Alzheimer’s disease.

“In my opinion, a good test for the hypothesis – especially with secretase inhibitors that decrease A? synthesis – would require treating patients very early in the disease, or even those who are asymptomatic.”

The tau hypothesis

A rival theory is the tau hypothesis. This has gained ground as evidence has failed to emerge showing a direct link between amyloid and the loss of neurons in the brain. Researchers now think the built up of tau in the brain proves to be toxic for cells, and causes them to die. The theory is further supported by similar disease known as tauopathies, in which the same protein is identifiably misfolded.

Closing in on the pathology

In December, new research was published which could represent a subtle but significant advance in our understanding of the disease. Randall Bateman, MD, an assistant professor of neurology at Washington University in St. Louis tested his hypothesis that Alzheimer’s sufferers produce normal amounts of beta-amyloid, but that it is not cleared or removed efficiently from the brain as it is normally.

The finding should help advance understanding of what pathways are most important in the development of Alzheimer’s pathology, and may one day lead to an improved biomarker to help provide earlier diagnosis as well as new treatments.

Dr. Bateman and his researchers used a study of cerebrospinal fluid (CSF) to measure beta-amyloid production, and clearance rates in study volunteers with Alzheimer’s disease and in age-matched volunteers free of the disease.

‘‘This study is significant in that it reports the first measurement of beta-amyloid production and clearance in Alzheimer’s,” said Marcelle Morrison-Bogorad, PhD, director of the Division of Neuroscience at the National Institute on Aging (NIA).

‘‘For years scientists believed that it was the overproduction of beta-amyloid that led to its accumulation in the brain. These new findings shift the emphasis to clearance of beta-amyloid. This may lead to development of a diagnostic test as well as identification of new therapeutic targets.”

Late-stage survivors

There are presently three disease-modifying drugs in phase III trials which could reach patients within the next few years. Lilly and Elan’s anti-beta-amyloid monoclonal antibody, solanezumab, is expected to complete phase III trials in April 2012.

Solanezumab binds specifically to soluble amyloid beta, and thereby may draw the peptide away from the brain through the blood. In earlier short-term clinical studies, solanezumab appeared to have dose-dependent effects on amyloid beta in blood and cerebrospinal fluid.

But these studies were too short to evaluate any potential delay in the progress of Alzheimer’s disease, something which Lilly hopes the phase III trials will provide.

Next is Pfizer/Medivation’s Dimebon (latrepirdine), a mitochondrial function modulator for use in severe Alzheimer’s.

Dimebon protects nerve cells in the brain against damage and death by ensuring the good functioning of their mitochondria, the cell’s energy centre. Medivation completed patient enrolment in November 2010 in the CONCERT study – a 12-month, phase III clinical trial in patients with mild-to-moderate Alzheimer’s evaluating the potential efficacy of Dimebon when added to ongoing treatment with Aricept (donepezil).

Top-line results from the CONCERT trial are expected in the first half of 2012. The FDA has confirmed that the company can use its phase III CONCERT trial to complete the registration package for mild-to-moderate Alzheimer’s disease, provided that the results are robustly positive.

Finally, there is bapineuzumab, being co-developed by Johnson & Johnson and Pfizer.

Bapineuzumab is an anti-beta-amyloid humanised monoclonal antibody. It binds to beta-amyloid molecules and removes them from the brain. This in turn prevents the formation of plaques, which, as we have seen, are considered central to the development and progression of the disease.

A study published last year in The Lancet found that in patients with mild or moderate Alzheimer’s disease, treatment with bapineuzumab reduced beta-amyloid in the brain by 25 per cent.

Subsequent research also showed that bapineuzumab lowers brain levels of the tau protein, giving it a second potential avenue for treating the disease. This could give the drug two opportunities to help Alzheimer’s patients.

Kaj Blennow, MD, PhD, of the University of Gothenburg, Sweden is the lead investigator at one of the global sites investigating bapineuzumab.

‘‘These observations suggest that immunotherapy treatment targeting amyloid may also alter neurodegenerative processes that occur later in the disease process and that are more directly associated with loss of function,” Blennow said. ‘‘However, this was a small study and these findings need to be confirmed.”

There are many more candidates currently in earlier clinical and pre-clinical development, but information about different mechanisms being studied is in short supply. Roche, the current leader in oncology is trying to expand its portfolio into CNS drugs, and has two drugs in phase II being studied for Alzheimer’s, (RG3487 and RG1450) and RG1662 for ‘cognitive disorders’, with a further Alzheimer’s candidate in phase I.

Genenetech, Roche’s standalone biotech arm also has an anti-beta-amyloid treatment in phase II.

Not the ‘magic bullet’

After so many disappointments, experts are careful not to be too bullish about these phase III hopefuls being a great step forward in treatment.

Professor John Hardy is professor of neuroscience and chair of molecular biology for neurological disease at University College London, and is credited as one of the originators of the amyloid hypothesis in the 1990s.

He says: “The answer to these questions depend primarily on whether or not there will be definite proof that the drugs under development actually work. Should this happen, it would be a major step forward compared to cholinesterase inhibitors, which only treat the symptoms of the disease.”

At present, however, he says many doubt that any of the drugs in the pipeline could represent an advance in treatment. “I think there is some pessimism that anything is ever going to change substantially for patients,” says Hardy.

“We all hoped that the results from the clinical trials on the new agents would show that these were going to be the ultimate therapy for Alzheimer’s disease” – only time will tell if this is the case or not.

Looking ahead, Hardy thinks any successfully launched new treatment will not instantly replace the current standard of treatment.

“The likely future scenario is that cholinesterase inhibitors will continue to be the drugs of choice for patients with Alzheimer’s disease, and investigational drugs will be used as adjunctive therapies – if proven effective. We are moving from the idea of a ‘magic bullet’ to the idea of polypharmacy, whereby different drugs will likely be used simultaneously, each one of which will make a small, but significant, difference in the patients’ lives.”

This is true for the majority of medical conditions, where the goal is to ensure the maximum benefit to patients. Hardy says: “Take type II diabetes, for instance. People with this condition are given insulin, which targets the cause of their condition. But they also take statins, which help reduce their hypercholesterolemia, one of the symptoms of their condition.”

Something similar will be possible for Alzheimer’s patients in the years to come.

Yet, whether or not the current phase III candidates prove to be successful, research must continue to fight the devastating effects of Alzheimer’s and its growing incidence around the world.

A ROLE FOR DIABETES DRUGS?

New research suggests that new diabetes drugs enhance cell growth in the brain, and could help treat Alzheimer’s disease.

Researchers at the University of Ulster in Coleraine funded by research charity the Alzheimer’s Research Trust, studied the effects of two drugs – Novo Nordisk’s Victoza (liraglutide) and Lilly’s Byetta (exenatide) – as part of an investigation into the link between diabetes and Alzheimer’s disease.

The drugs mimic a hormone called GLP-1, which helps the body produce insulin. But the team at Ulster, led by Dr Christian Hölscher, found that in mice with diabetes, the drugs also stimulated the growth of new brain cells.

They now hope their findings, published in the Journal of Neuroscience Research, could help scientists in the search for a potential treatment for Alzheimer’s.

Further research by the same team found that in mice with Alzheimer’s, liraglutide enhanced brain cell growth and reduced the build-up of a protein called amyloid in the brain – a key feature of the disease – as well as protecting the formation of memories.

Dr Hölscher, who presented his latest findings at the prestigious Society for Neurosciences annual meeting, said: “It has been known for some time that diabetes is a risk factor for developing Alzheimer’s disease, and we know that in diabetes, the growth and replacement of cells in the brain are compromised, putting the brain at risk of further damage.

“We are very excited about our results, which show that these drugs are able to enter the brain, where they can help protect and replace cells. Because the drugs are already approved for use in people, this is a rich field for future research, and we would now like to see clinical trials to test the effects of these drugs in people with Alzheimer’s.”

http://www.inpharm.com/news/150663/late-stage-alzheimers-disease-research

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