Latrepirdine ( also known as dimebolin and sold as Dimebon), is an antihistamine drug which has been used clinically in Russia since 1983.

Research is continuing in both Russia and western nations into potential applications as a neuroprotective drug to combat Alzheimer’s disease and, possibly, as a nootropic as well.However, a Phase III clinical trial for Alzheimer’s disease (AD) treatment failed to show any benefit. Three other AD trials continue. Dimebon failed in the phase III trial for Huntington disease.

Uses

Latrepirdine is an orally-active small molecule compound that has been shown to inhibit brain cell death in animal models of Alzheimer’s disease and Huntington’s disease. Research suggests that it may also have cognition-enhancing effects in healthy individuals, in the absence of neurodegenerative disease pathology.  However, because of negative results in human clinical trials, the drug remains unlicensed for any neurodegenerative condition.

http://en.wikipedia.org/wiki/Latrepirdine

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Dimebon Dimebolin Information Availability

US biotech firm Medivation (Nasdaq: MDVN) says that patient enrollment was completed at end November in the CONCERT study, a 12-month, Phase III clinical trial in patients with mild-to-moderate Alzheimer’s disease evaluating the potential efficacy of Dimebon (latrepirdine) when added to ongoing treatment with donepezil.

Medivation is conducting this study under its collaboration agreement with drug behemoth Pfizer (NYSE: PFE) which acquired rights the product in 2008 in a deal worth a potential $725 million ($225 million upfront) to the former company.

Dimebon – an old Russian antihistamine approved in that market in 1983 – had once been touted as a blockbuster drug for AD, with potential for anything between $1.5 billion and $5 billion annual sales. However, earlier this year, the majority of observers wrote it off after – somewhat unexpectedly – it failed to meet co-primary or secondary efficacy endpoints compared to placebo in two Phase III trials (The Pharma Letter March 4). After the disastrous results, Medivation’s shares cratered and have yet to recover from the beating they received.

Has received FDA feedback

“Completing patient enrollment in CONCERT is an important step forward for our Dimebon development program in Alzheimer’s disease,” said Lynn Seely, chief medical officer of Medivation. “Now that enrollment is complete, we expect to report top-line results from the CONCERT trial in the first half of 2012. We have previously received feedback from the FDA [Food and Drug Administration] confirming that we can use our Phase III CONCERT trial to complete our registration package for mild-to-moderate Alzheimer’s disease, provided that the results are robustly positive,” she added.

The international, randomized, double-blind, placebo-controlled Phase III CONCERT trial  enrolled 1,003 patients with mild-to-moderate AD at approximately 100 sites in the USA, Australia, New Zealand and Western Europe. Patients on a stable dose of donepezil were randomized to one of three treatment groups: Dimebon 20mg three times per day, Dimebon 5mg three times per day or placebo. Patients were required to be on treatment with donepezil for at least six months and at a stable dose of 10mg daily for at least four months prior to enrollment in the study. The primary endpoints are the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) – a measure of self-care and daily function.

http://www.thepharmaletter.com/file/100475/medivation-persists-with-dimebon-research-in-alzheimers-despite-earlier-failures.html

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Dimebon Dimebolin Information Availability

Description

Background

Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer’s disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD.

Results

The present studies are designed specifically to assess whether dimebon might modulate ?-amyloid (A?)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total A? as well as soluble oligomeric A? in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon.

Conclusion

Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer’s disease-type A?-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington’s disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function.

http://www.molecularneurodegeneration.com/content/6/1/7/abstract

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Dimebon Dimebolin Information Availability

Global drug behemoth Pfizer (NYSE: PFE) and partner Medivation (Nasdaq: MDVN) said yesterday that results from the Phase III HORIZON trial of the investigational drug Dimebon (latrepirdine) in patients with Huntington disease did not achieve statistical significance for either of the co-primary endpoints of the study.

Dimebon, which is an old Russian antihistamine approved in that market in 1983, had previously been touted as a blockbuster drug with a sales potential of anything between $1.5 billion and $5 billion in the treatment of Alzheimer’s disease. However, despite positive Phase II trial results, last year it failed to meet co-primary and secondary endpoints in AD in two Phase III studies (The Pharma Letter March 4, 2010).

Development to continue  in Alzheimer’s, says Medivation

“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, and chief executive of Medivation. “We will continue our ongoing 12-month Phase III 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,” he added.

Dimebon was generally well tolerated in the HORIZON trial, consistent with findings from previous trials including over 2,000 patients, the large majority of whom were Alzheimer’s disease patients.

“Huntington’s is a challenging disease area, and we are also disappointed with the HORIZON results,” said Pfizer’s Steve Romano, senior vice president, Medicines Development Group head, Primary Care Business Unit, noting that the results are expected to be presented at an upcoming medical meeting.

HORIZON study design and results

The double-blind, placebo-controlled Phase III HORIZON trial enrolled 403 patients with Huntington disease at 64 sites in North America, Europe and Australia. The trial included patients who had cognitive impairment, based on investigator judgment and verified by MMSE score. Patients were randomized to receive either 20mg of Dimebon three times daily or placebo for six months.

No statistically significant improvements were achieved for the Dimebon group relative to placebo on either of the co-primary endpoints. Dimebon was generally well tolerated in the study. The overall incidence of adverse events was equivalent between the treatment groups: 69% in the Dimebon group and 68% in the placebo arm.

http://www.thepharmaletter.com/file/103545/pfizer-and-medivations-dimebon-also-flops-in-huntington-disease.html

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Dimebon Dimebolin Information Availability

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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Dimebon

Background

Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer’s disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD.

Results

The present studies are designed specifically to assess whether dimebon might modulate ?-amyloid (A?)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total A? as well as soluble oligomeric A? in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon.

Conclusion

Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer’s disease-type A?-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington’s disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function.

http://www.molecularneurodegeneration.com/content/6/1/7/abstract

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Background

Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer’s disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD.

Results

The present studies are designed specifically to assess whether dimebon might modulate ?-amyloid (A?)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total A? as well as soluble oligomeric A? in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon.

Conclusion

Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer’s disease-type A?-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington’s disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function.

http://www.molecularneurodegeneration.com/content/6/1/7/abstract

Winnipeg Alternative Therapies

A potential Alzheimer’s drug that had seemed to perform spectacularly well in a medium-scale clinical trial has now been shown in a larger and more conclusive trial to have no apparent effect on the disease.

The surprising failure of the drug, known as dimebon, is yet another disappointment for Alzheimer’s researchers as well as patients and their families. It also raises questions about the conduct and design of Alzheimer’s clinical trials, particularly in Russia where the initial dimebon trial took place.

“The prior doubts about the Russian trial appear to have been borne out,” says Sam Gandy, an Alzheimer’s researcher at Mount Sinai School of Medicine.

Dimebon (generic name latrepirdine) was originally developed and briefly used as an antihistamine in Russia in the 1980s. It began to be re-evaluated as a potential Alzheimer’s drug in the 1990s, after Russian researchers reported that it seemed to boost the levels of memory-related neurotransmitters in lab tests on brain cells.

A San Diego-based company, Medivation, Inc., eventually began clinical trials of dimebon in Russia, where the drug was already approved for use. In 2008, astounding results were reported in 183 Russian patients whose Alzheimer’s dementia was classified as “mild-to-moderate.” Half had received dimebon at a dose of 20 mg thrice daily, and half had received a thrice-daily placebo. After six months, the dimebon group scored much higher on standard tests of cognition and quality of life, and follow-up studies suggested that the progression of the disease had been stopped. The apparent “treatment effect” was the largest ever reported for an Alzheimer’s drug trial.

Some researchers expressed concern that such a powerful result was too good to be true, particularly since no one really knew how dimebon worked against Alzheimer’s. However, several well-known U.S. clinical trial experts had observed the Russian study and vouched for its validity. Other researchers soon reported evidence from laboratory studies that dimebon might be able to boost the general survival ability of neurons in a way that could make them resistant to other neurodegenerative diseases too (see “Hope and Caution on Russian Antihistamine Drug for Alzheimer’s”).

Unfortunately, dimebon seemed only weakly effective in a small-scale clinical trial in people with Huntington’s disease; its results were reported in February. And on March 3, dimebon’s candidacy as an Alzheimer’s drug was most likely terminated.

On that day, Medivation reported results from a large, apparently definitive trial of dimebon in 598 people with Alzheimer’s in North America, South America, and Europe. Those results suggest that dimebon, while safe, is completely ineffective against Alzheimer’s disease. The data failed to show even a hint of a consistent impact on patients’ cognition and quality of life, compared to a placebo.

In recent years, a number of Western drug companies have used Russian hospitals as a relatively inexpensive proving ground for early-stage drug development. However, in at least one other case, a positive result from a Russian trial has failed to translate to a larger, more rigorous Western trial.

Gandy says he wonders whether “something is systematically wrong over there.”

In the case of dimebon, not only the early clinical trial results but also a significant amount of laboratory work appears to be of questionable value. Over the past few years, researchers who were eager to find dimebon’s mechanism of action against dementia have reported, for example, that it blocks the toxicity of amyloid beta aggregates found in Alzheimers, or that it enhances the survival of mitochondria. If nothing else, the case underscores the weakness of such laboratory evidence in the absence of data in people that confirms it.

“At the moment I don’t think that any of these effects is clinically important,” said Gandy, whose own research group recently found that dimebon actually increases amyloid beta levels outside cells, in lab dish and animal experiments.

To some researchers, the dimebon failure, and the failure of many other Alzheimer’s drug candidates to date, points to a larger problem:  The treatments are started too late in the course of the disease.

“What you want in such trials are people who are just starting to lose neurons, but typically by the time an Alzheimer’s patient goes to see a neurologist, his or her brain has already been severely damaged,” says Jeffery Kelly, an investigator at the Scripps Research Institute in La Jolla, California, whose work has focused on amyloid-associated conditions. “Considering the way the Alzheimer’s trials are being done now, I’m not sure that even a great drug could be discerned as such.”

Gandy agrees:  “I think that our best chance for impact on this disease is presymptomatic intervention and prevention.”

http://www.dana.org/news/features/detail.aspx?id=25798

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Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer’s disease (AD). Results from several completed clinical trials are mixed and contradictory.

Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD.

Results: The present studies are designed specifically to assess whether dimebon might modulate beta-amyloid (Abeta)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration.

AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total Abeta as well as soluble oligomeric Abeta in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon.

Conclusion: Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer’s disease-type Abeta-related mechanisms or global energy metabolism in the brain.

Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington’s disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function.

http://www.dimebonalzheimers.com/

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