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

Winnipeg Alternative Therapies

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Top-line results of 2 phase 3 trials of latrepirdine (Dimebon, Medivation/Pfizer) show that the drug failed to meet either primary or secondary endpoints vs placebo for the treatment of Alzheimer’s disease (AD).

The results have caused not only disappointment but some skepticism now about the original phase 2 results with latrepirdine, published in the Lancet in 2008, which had shown extremely positive response to the drug.

The CONNECTION trial, a randomized, phase 3, multicenter trial of

almost 600 patients with AD, showed no difference between those receiving 20 mg 3 times daily of latrepirdine vs placebo on the coprimary endpoints of change from baseline on either cognition, measured with the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog), or global function, measured with the Clinician’s Interview–Based Impression of Change Plus Caregiver Input (CIBIC+), after 6 months of treatment.

Results of a separate phase 3 trial with the aim of assessing the safety and tolerability of latrepirdine in combination with other approved AD medications, including cholinesterase inhibitors, memantine or both, were released at the same time. The results confirmed the safety of combining latrepirdine with other medications, although now to an uncertain end.

“The results from the CONNECTION study are unexpected and obviously a major disappointment for all of us, especially for Alzheimer’s disease patients and their caregivers,” David Hung, MD, president and chief executive office of Medivation, which is developing the drug in collaboration with Pfizer, said in a telephone conference call.

The top-line results were released March 3, and full data are expected to be presented at an upcoming medical meeting, Dr. Hung noted, although he did not specify which.

CONNECTION Trial

CONNECTION was a phase 3, multinational, double-blind safety and efficacy trial conducted at 63 sites in North America, Europe, and South America. A total of 598 patients with mild to moderate AD were randomized to 1 of 2 doses of latrepirdine (20 mg or 5 mg 3 times daily) or placebo. The 5-mg 3 times daily dose had been included to define the effective dose range, the company noted.

Patients included had a mean age of 74 years and a mean score of 17.7 on the Mini-Mental State Examination (MMSE) at baseline.

After 6 months of treatment, no difference was seen between the group receiving latrepirdine, 20 mg 3 times daily, and placebo. On the ADAS-cog, treated patients achieved a nonsignificant 0.1-point difference from those taking placebo (P = .86), and neither group was significantly changed from baseline. No difference either was seen in independently rated global function on the CIBIC+; 64.9% of patients taking latrepirdine, 20 mg, showed improvement or no change at week 26 vs 65.4% among those taking placebo (P = .81).

Similarly, there were no differences on secondary efficacy endpoints. Patients taking latrepirdine showed a nonsignificant difference of 0.4 point from those taking placebo on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale (P = .61), although, again, neither group changed significantly from baseline.

The Neuropsychiatric Inventory (NPI) showed a 1.6-point improvement in behavior for treated patients over placebo (P = .17); both groups improved over baseline on this measure, but the change was only significant for the latrepirdine group.

However, on the MMSE, both groups improved significantly over baseline, and the improvement was actually greater, although not significantly, with placebo (latrepirdine, 0.7; placebo, 1.2; P = .10).

The 20-mg dose was well tolerated, with similar numbers of patients having at least 1 adverse event (72.0% with latrepirdine vs 74.2% with placebo). The most frequently reported adverse events with latrepirdine occurring more commonly than in placebo were somnolence, dry mouth, headache, dizziness, constipation, cough, and depression.

In the separate phase 3 safety and tolerability study, 742 patients with mild-to-moderate AD from the United States and Canada were randomized to receive either 20 mg 3 times daily of latrepirdine or placebo, with treatment for either 3 or 6 months. Approximately 85% of patients were already taking an approved AD medication.

The drug was well tolerated, the companies reported. The most frequently reported adverse events in the latrepirdine group occurring more commonly than with placebo were somnolence and fatigue.

Lancet Phase 2 Study?

The new results are at odds with those previously reported in a phase 2 trial published in the Lancet in 2008 by lead investigator Rachelle Doody, MD, PhD, professor of neurology at Baylor College of Medicine in Houston, Texas, and colleagues (Doody R, et al. Lancet. 2008;372:207-215).

The drug had originally been developed as an antihistamine in Russia, and so the phase 2 trial was performed at 11 centers there, although under the direction of US clinical trialists.

In that trial, patients with mild to moderate AD who were taking the drug showed impressive and significant improvements across all domains measured; cognitive function, memory, ability to perform tasks of daily living, global function, and behavior, which increased and then were sustained over time.

“At this point we are keenly focused on 2 key questions,” Dr. Hung said on the conference call. “First, why are the results from CONNECTION so different from those seen in the Lancet trial, and second, what are the implications of these for the ongoing development of Dimebon for Alzheimer’s and Huntington’s diseases?”

To the first question, he noted that “the 2 biggest differences we saw between the 2 trials were, first, response to Dimebon treatment was materially weaker in CONNECTION than in the Lancet, and second, we saw a placebo response in CONNECTION that we did not see” in that previous paper.

For example, in the 20-mg 3 times daily dose studied in both trials, latrepirdine patients were significantly improved over baseline scores on all 5 efficacy endpoints after 6 months of treatment. In CONNECTION, treated patients were significantly improved over baseline in only 2 of the 5 endpoints, the NPI and the MMSE.

On the ADAS-cog, a coprimary endpoint, latrepirdine-treated patients improved by 1.9 points in the phase 2 trial vs a decrease of 0.2 point in CONNECTION, he noted. On the CIBIC+, the other coprimary endpoint, 81% of latrepirdine-treated patients were improved or unchanged in the phase 2 trial, whereas the corresponding number in CONNECTION was 65%.

In the phase 2 study, placebo-treated patients decline significantly from baseline scores on all 5 efficacy endpoints by 6 months, but in the phase 3 study, there was no decline in the placebo patients on any of these endpoints and, in fact, some improvement in the MMSE. Decline in the placebo patients was consistent between the studies for mild AD patients, but those with moderate disease had decreased by 3.9 ADAS-cog points in the phase 2 study vs only 1.1 points in CONNECTION.

“A placebo response in the normal range would not have changed the outcome of the CONNECTION study,” Dr. Hung said. “However, we believe it is worthwhile to analyze the reasons behind this response as part of our process for determining appropriate next steps for the development of Dimebon.”

Trials Ongoing, for Now

Four phase 3 trials are still ongoing and enrolling at this point in AD and Huntington’s disease, Dr. Hung said. These include the following:

• The CONCERT trial, a 12-month study testing latrepirdine in patients with mild-to-moderate AD who are taking donepezil;
• The CONTACT and CONSTELLATION trials, 6-month trials of latrepirdine in patients with moderate-to-severe AD also taking donepezil and memantine, respectively.
• The HORIZON trial, a 6-month study of latrepirdine in patients with Huntington’s disease.

In February, results of another trial using latrepirdine in Huntington’s disease, the DIMOND trial, showed some positive effect on cognition in this population (Kieburtz K, et al. Arch Neurol. 2010;67:154-160).

Dr. Hung concluded by pointing out that Medivation and Pfizer have already undertaken more comprehensive analysis of the CONNECTION data, with an eye to determine whether they will have any impact on the ongoing development program for the drug.

“This will be a complex analysis that will encompass scientific, clinical, and business issues,” he said. “We recognize this as an urgent task. We will proceed accordingly and update you when decisions are reached.”

http://www.medscape.com/viewarticle/718401

http://www.dimebonalzheimers.com/

Winnipeg Alternative Therapies

Top-line results of 2 phase 3 trials of latrepirdine (Dimebon, Medivation/Pfizer) show that the drug failed to meet either primary or secondary endpoints vs placebo for the treatment of Alzheimer’s disease (AD).

The results have caused not only disappointment but some skepticism now about the original phase 2 results with latrepirdine, published in the Lancet in 2008, which had shown extremely positive response to the drug.

The CONNECTION trial, a randomized, phase 3, multicenter trial of almost 600 patients with AD, showed no difference between those receiving 20 mg 3 times daily of latrepirdine vs placebo on the coprimary endpoints of change from baseline on either cognition, measured with the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog), or global function, measured with the Clinician’s Interview–Based Impression of Change Plus Caregiver Input (CIBIC+), after 6 months of treatment.

Results of a separate phase 3 trial with the aim of assessing the safety and tolerability of latrepirdine in combination with other approved AD medications, including cholinesterase inhibitors, memantine or both, were released at the same time. The results confirmed the safety of combining latrepirdine with other medications, although now to an uncertain end.

“The results from the CONNECTION study are unexpected and obviously a major disappointment for all of us, especially for Alzheimer’s disease patients and their caregivers,” David Hung, MD, president and chief executive office of Medivation, which is developing the drug in collaboration with Pfizer, said in a telephone conference call.

The top-line results were released March 3, and full data are expected to be presented at an upcoming medical meeting, Dr. Hung noted, although he did not specify which.

CONNECTION Trial

CONNECTION was a phase 3, multinational, double-blind safety and efficacy trial conducted at 63 sites in North America, Europe, and South America. A total of 598 patients with mild to moderate AD were randomized to 1 of 2 doses of latrepirdine (20 mg or 5 mg 3 times daily) or placebo. The 5-mg 3 times daily dose had been included to define the effective dose range, the company noted.

Patients included had a mean age of 74 years and a mean score of 17.7 on the Mini-Mental State Examination (MMSE) at baseline.

After 6 months of treatment, no difference was seen between the group receiving latrepirdine, 20 mg 3 times daily, and placebo. On the ADAS-cog, treated patients achieved a nonsignificant 0.1-point difference from those taking placebo (P = .86), and neither group was significantly changed from baseline. No difference either was seen in independently rated global function on the CIBIC+; 64.9% of patients taking latrepirdine, 20 mg, showed improvement or no change at week 26 vs 65.4% among those taking placebo (P = .81).

Similarly, there were no differences on secondary efficacy endpoints. Patients taking latrepirdine showed a nonsignificant difference of 0.4 point from those taking placebo on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale (P = .61), although, again, neither group changed significantly from baseline.

The Neuropsychiatric Inventory (NPI) showed a 1.6-point improvement in behavior for treated patients over placebo (P = .17); both groups improved over baseline on this measure, but the change was only significant for the latrepirdine group.

However, on the MMSE, both groups improved significantly over baseline, and the improvement was actually greater, although not significantly, with placebo (latrepirdine, 0.7; placebo, 1.2; P = .10).

The 20-mg dose was well tolerated, with similar numbers of patients having at least 1 adverse event (72.0% with latrepirdine vs 74.2% with placebo). The most frequently reported adverse events with latrepirdine occurring more commonly than in placebo were somnolence, dry mouth, headache, dizziness, constipation, cough, and depression.

In the separate phase 3 safety and tolerability study, 742 patients with mild-to-moderate AD from the United States and Canada were randomized to receive either 20 mg 3 times daily of latrepirdine or placebo, with treatment for either 3 or 6 months. Approximately 85% of patients were already taking an approved AD medication.

The drug was well tolerated, the companies reported. The most frequently reported adverse events in the latrepirdine group occurring more commonly than with placebo were somnolence and fatigue.

Lancet Phase 2 Study?

The new results are at odds with those previously reported in a phase 2 trial published in the Lancet in 2008 by lead investigator Rachelle Doody, MD, PhD, professor of neurology at Baylor College of Medicine in Houston, Texas, and colleagues (Doody R, et al. Lancet. 2008;372:207-215).

The drug had originally been developed as an antihistamine in Russia, and so the phase 2 trial was performed at 11 centers there, although under the direction of US clinical trialists.

In that trial, patients with mild to moderate AD who were taking the drug showed impressive and significant improvements across all domains measured; cognitive function, memory, ability to perform tasks of daily living, global function, and behavior, which increased and then were sustained over time.

“At this point we are keenly focused on 2 key questions,” Dr. Hung said on the conference call. “First, why are the results from CONNECTION so different from those seen in the Lancet trial, and second, what are the implications of these for the ongoing development of Dimebon for Alzheimer’s and Huntington’s diseases?”

To the first question, he noted that “the 2 biggest differences we saw between the 2 trials were, first, response to Dimebon treatment was materially weaker in CONNECTION than in the Lancet, and second, we saw a placebo response in CONNECTION that we did not see” in that previous paper.

For example, in the 20-mg 3 times daily dose studied in both trials, latrepirdine patients were significantly improved over baseline scores on all 5 efficacy endpoints after 6 months of treatment. In CONNECTION, treated patients were significantly improved over baseline in only 2 of the 5 endpoints, the NPI and the MMSE.

On the ADAS-cog, a coprimary endpoint, latrepirdine-treated patients improved by 1.9 points in the phase 2 trial vs a decrease of 0.2 point in CONNECTION, he noted. On the CIBIC+, the other coprimary endpoint, 81% of latrepirdine-treated patients were improved or unchanged in the phase 2 trial, whereas the corresponding number in CONNECTION was 65%.

In the phase 2 study, placebo-treated patients decline significantly from baseline scores on all 5 efficacy endpoints by 6 months, but in the phase 3 study, there was no decline in the placebo patients on any of these endpoints and, in fact, some improvement in the MMSE. Decline in the placebo patients was consistent between the studies for mild AD patients, but those with moderate disease had decreased by 3.9 ADAS-cog points in the phase 2 study vs only 1.1 points in CONNECTION.

“A placebo response in the normal range would not have changed the outcome of the CONNECTION study,” Dr. Hung said. “However, we believe it is worthwhile to analyze the reasons behind this response as part of our process for determining appropriate next steps for the development of Dimebon.”

Trials Ongoing, for Now

Four phase 3 trials are still ongoing and enrolling at this point in AD and Huntington’s disease, Dr. Hung said. These include the following:

• The CONCERT trial, a 12-month study testing latrepirdine in patients with mild-to-moderate AD who are taking donepezil;
• The CONTACT and CONSTELLATION trials, 6-month trials of latrepirdine in patients with moderate-to-severe AD also taking donepezil and memantine, respectively.
• The HORIZON trial, a 6-month study of latrepirdine in patients with Huntington’s disease.

In February, results of another trial using latrepirdine in Huntington’s disease, the DIMOND trial, showed some positive effect on cognition in this population (Kieburtz K, et al. Arch Neurol. 2010;67:154-160).

Dr. Hung concluded by pointing out that Medivation and Pfizer have already undertaken more comprehensive analysis of the CONNECTION data, with an eye to determine whether they will have any impact on the ongoing development program for the drug.

“This will be a complex analysis that will encompass scientific, clinical, and business issues,” he said. “We recognize this as an urgent task. We will proceed accordingly and update you when decisions are reached.”

“Absolutely Zero Effect”

Medscape Neurology polled some AD experts on their reaction to the new results.

http://www.medscape.com/viewarticle/718401

http://www.dimebonalzheimers.com/

Winnipeg Alternative Therapies

Winnipeg Manitoba  Mainstay Hotels

A survey of neurologists in Europe has shown only a minority are aware of late stage drugs being developed to treat Alzheimer’s – and some are skeptical about the likely efficacy of one of the drugs.

Market research analysts Decision Resources interviewed 256 neurologists and 15 payors across, France, Germany, Italy, Spain and the UK, and found that most were unaware of the drugs now in phase III.

Three drugs are currently in late stage development – Pfizer/Medivation’s mitochondrial function modulator Dimebon and J&J/Pfizer’s anti-beta-amyloid monoclonal antibody (MAb) bapineuzumab, and Lilly’s anti-beta-amyloid MAb solanezumab.

Between 26 and 42% said they were familiar with Dimebon and bapineuzumab, while between 20-28% were familiar with solanezumab.

Developing new treatments for Alzheimer’s is notoriously difficult, and there have been numerous late stage casualties recently, including another Lilly drug, semagacestat.

“The finding that similar percentages of surveyed neurologists overall expect to prescribe solanezumab and bapineuzumab is not necessarily surprising, as these agents have similar mechanisms of action,” said Decision Resources analyst Georgiana Kuhlmann, MSc.

The survey suggested that neurologists believed solanezumab would capture slightly more patient share than bapineuzumab in mild Alzheimer’s disease patients, while bapineuzumab would be prescribed to patients with more moderate Alzheimer’s disease patients.

Decision Resources says this difference could reflect a perception that solanezumab has the better safety profile compared with bapineuzumab, but adds that: “This perception remains to be borne out in ongoing phase III trials”.

The survey also confirmed that neurologists prescribe cholinesterase inhibitors, such as Eisai and Pfizer’s Aricept to patients in all stages of the disease.  The neurologists said they expected pressure from reimbursement authorities to use generic versions of cholinesterase inhibitors once they become available.

Aricept is due to lose its patent in most European countries in February 2012.

This feeling was particularly marked in Germany, where the generics market is already the largest in Europe, and where doctors have strict prescribing budgets. Nearly two-thirds of neurologists in the UK and Spain expect pressure from reimbursement authorities to prescribe generic AChEIs as a way to control costs.

Notably fewer neurologists expect to prescribe Dimebon, a perception probably related to scepticism about the drug’s efficacy. The drug suffered a well-publicised setback this year.

The report entitled European Clinician and Payer Receptivity to Novel Agents for Alzheimer’s Disease also found that neurologists felt they were equally likely to prescribe solanezumab and bapineuzumab if they were approved in Europe, which the analysts say suggests the drugs are not yet strongly differentiated in the minds of prescribers.

http://www.inpharm.com/news/101117/europe-neurologists-alzheimers-drugs

Dimebon

http://www.dimebonalzheimers.com/

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]]> http://dimebonalzheimers.com/657/europes-neurologists-unfamiliar-emerging-alzheimers-drugs/feed/ 0 http://dimebonalzheimers.com/396/medivation-pfizer-disappointed-over-drug-failure-biotechs-latest-mishaps/ http://dimebonalzheimers.com/396/medivation-pfizer-disappointed-over-drug-failure-biotechs-latest-mishaps/#comments Fri, 21 May 2010 14:36:03 +0000 admin http://www.dimebonalzheimers.com/?p=396
Pfizer (PFE) and Medivation (MDVN) said dimebon, their experimental drug to treat Alzheimer’s disease, failed in two late-stage clinical trials. Medivation’s stock, which had been trading at an all time high of $40.49 right before the news, tumbled nearly 70 percent to $13.04. In one trial, dimebon did not show statistical significance compared to placebo [...]



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Pfizer (PFE) and Medivation (MDVN) said dimebon, their experimental drug to treat Alzheimer’s disease, failed in two late-stage clinical trials. Medivation’s stock, which had been trading at an all time high of $40.49 right before the news, tumbled nearly 70 percent to $13.04. In one trial, dimebon did not show statistical significance compared to placebo in measures of cognition and global function – the primary endpoints for the study. The results were surprising because early studies had produced promising results of the drug as a treatment for the neurodegenerative disease. A separate phase 3 safety and tolerability study found dimebon was well tolerated when given alone or in combination with a variety of other Alzheimer’s disease medicines, including cholinesterase inhibitors, memantine, or both. Previous studies have confirmed the tolerability of dimebon alone. Pfizer said it is evaluating the data from the trials and will determine appropriate next steps regarding the dimebon program when that process is completed.

Researchers have reported promising results for a new Alzheimer’s drug. We take a close look at the evidence, to see whether it might offer a new option for treatment.

What is Known At this Point in Time for the Treatment of Alzheimer’s Disease ?

Alzheimer’s disease is the most common cause of dementia in older people. If someone has dementia, they have trouble with memory and thinking. Their behavior often changes, and eventually they become unable to look after themselves.

There are several treatments to help with the symptoms of dementia, although none of them can cure it. Drugs called cholinesterase inhibitors seem to slow the progress of dementia in some people. However, there’s been a lot of controversy about how well these drugs work.

The National Institute for Health and Clinical Excellence (NICE) is the organisation that decides which treatments can be offered on the NHS. NICE says that three different cholinesterase inhibitors can be used on the NHS, but only for people with moderate Alzheimer’s disease. The drugs aren’t recommended for people in the early stages of Alzheimer’s.

Dementia is likely to be a big problem in future years, as people are living longer on average, so are more likely to get dementia. Doctors are looking for more treatments that may be useful for dementia. One drug being studied at the moment is called dimebon. It’s an antihistamine that was once used to treat allergies. But it was dropped when other allergy drugs were developed. Now, doctors are looking to see if it’s helpful for Alzheimer’s disease.

What does the new study say?

Dimebon worked better than a dummy (placebo) drug for people with mild to moderate Alzheimer’s disease, over six months to a year. People taking dimebon had improved test scores for thinking and memory. People taking the placebo had scores that got worse over the course of the study.

Researchers found the same results using several different tests, all of which looked mainly at how well people could think and remember things.

Tell me more about the study’s findings

The improvement in test scores happened mostly in the first three to six months of the study. Towards the end of 12 months, the average test scores for people taking dimebon had started to go down. But, because the test scores for people who took a placebo went down steadily during the whole 12 months, the people taking dimebon did much better by comparison at the end of the year.

It’s hard to know exactly what the test scores mean. The main test used has a maximum of 70 points. People taking dimebon did about 4 points better than people taking placebo after six months, and 7 points better after a year. That’s a big enough difference for a doctor to notice. But it’s hard to say what that means for the patient. For example, we don’t know whether it would mean someone could stay in their own home, rather than needing care in a nursing home.

People in the study didn’t get many serious side effects from dimebon. A dry mouth was the most common side effect.

Where does the study come from?

The study was carried out in Moscow, Russia, but overseen by researchers at the Baylor College of Medicine in Houston, Texas. It was published in The Lancet, a medical journal owned by a publishing company called Elsevier. It was funded by Medivation, the US company that makes and wants to sell dimebon. It’s quite common for medicine manufacturers to fund medical trials of their drugs.

How reliable are the findings?

The trial was carried out carefully, and over enough time that it should show a real result. It was a type of study called a randomised controlled trial, which is the best sort of study to see if one drug works better than another, or better than a placebo. However, there are some things that should make us cautious.

• It’s not a very big study. Only 183 patients took part.
• All the patients were in Russian hospitals. Treatment of Alzheimer’s disease is quite different in Russia, compared to the UK. People tend to be in big wards, in hospitals, and the drugs used in the UK are not widely available. So it’s hard to know whether these results would be the same if the drug was tested in the UK.

The study didn’t compare dimebon with existing drugs for Alzheimer’s disease. It seems to be better than no treatment at all, but we can’t say whether it’s better or worse than the drugs we have already.

What does this mean for me?

If you have Alzheimer’s, or you are caring for someone with the disease, you’ll probably be keen to hear about any potential new treatment. This new study gives some hope that dimebon might be a useful option. But we need to see more research to be sure. Even if more studies show it works well, it’s likely to be several years before dimebon is available as a treatment for Alzheimer’s.

Current Choice Actions for Friends & Family Suffering from Alzheimer’s Disease Dementia

There’s no need to take any action as a result of this study. If you care for someone with Alzheimer’s disease and are worried about their treatment, see your doctor. There are currently three drugs approved in the UK to treat moderate Alzheimer’s. They’re called donepezil, galantamine and rivastigmine.

http://www.guardian.co.uk/lifeandstyle/besttreatments/2008/jul/18/new-alzheimers-treatment-tested

Dimebon Alzheimer’s Disease

http://www.dimebonalzheimers.com

The cholinteresterase inhibitors thus far available  are currently only approved by the F.D.A. (The US Food and Drug Administration)  , are approved by the FDA as only being effective for Alzherimer patients who have thus far mild to moderate disease.  However these drugs and medications – that is the cholinesterase classification medication grouping, may well show promise for those who are in the earliest as well as later stages of the disease , as well.  In addition they could well be of benefit and benefits to those with mil cognitive impairment as well.

One large study evaluated the use of Aricept (dozepezil) in the treatment of mild cognitive  impairment and found that it significantly reduced conversion to active Alzheimer’s progressive disease.

Current Treatment for Alzheimer’s Disease – Prescription cholinesterase inhibitors include Exelon and Aricept. These drugs have varying side effects and can have contraindications with other medication, so it can be difficult for doctors to find the right pharmaceutical match and …

Methods and compositions using cholinesterase inhibitors – The invention provides methods for treating and/or preventing Alzheimer’s disease, psychiatric illnesses, encephalitis, meningitis, fetal alcohol syndrome, Karsakoff’s syndrome, anoxic brain injury, cardiopulmonary resuscitation …

alzheimer disease – These drugs are called cholinesterase inhibitors because they inhibit the enzymes that break down acetylcholine (acetylcholinesterase and butyrylcholinesterase). Some drugs target only acetylcholinesterase, whereas some target both …

Galantamine: Welsh daffodils containing galantamine may help fight … – Galantamine is a competitive and reversible cholinesterase inhibitor. It is believed it works by enhancing cholinergic function by increasing the concentration of acetylcholine in the brain. The atomics resolution 3D structure of the …

Cholinesterase Inhibitors Reduce Aggression, Wandering And … – Cholinesterase Inhibitors Reduce Aggression, Wandering And Paranoia In Alzheimer’s Disease.

While cholinesterase inhibitors are now believed to he most helpful in persons with severe Alzheimer’s disease ,sometimes patients can be maintained on these classes and classifications of drugs indefinitely due to the fact and observation that in clinical practice , that often patients who stop taking these drugs or types of medications deteriorate rapidly when the drugs are arbitrarily stopped or withdrawn.  Indeed there is new and upcoming evidence from studies that suggest that stopping cholinesterase inhibitors will result in decline in functioning to a level that the patient would have been at it they – he or she – had not been taking the drug in the first place.

In addition drugs in this class appear to have an added benefit in improving behaviour as well as overall cognitive abilities.

Dimebon Alzheimer?s Disease

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Perhaps the most prescribed category of drugs for Alzhimer’s disease are the “Cholinesterase Inhibitor”  branch.  This group and grouping includes four medications.  Their trade names are “Aricept” , “Cognex” , “Excelon”  and “Reminyl”.  This group of medications , specifically the  “Cholinterase Inhibitors”   work via a mechanism of raising brain levels of the chemical neurotransmitter in the brain , acetylcholine , that is deficient in people and patients who exhibit the signs , symptoms and progression of Alzheimer’s Disease and its variants.

It can be said that overall these drugs , and this classification of medications , work to slow the progression of Alzheimer’s Disease.

In terms of side effects , and the range and variations of side effects with the Cholinesterase classification of drugs  side effects are all pretty similar in their type and range.  This generally includes , nausea , vomiting ,diarrhea , stomach pain, and loss of appetite.  However care must be exhibited with the drug / medication Cognex which can work to effect and cause liver toxicity and toxicities.

Dimebon Alzheimer?s Disease

http://www.dimebonalzheimers.com