Results from a series of trials on four drugs to treat Alzheimer’s appear to bring a new era of hope to patients with the disease, according to scientists reporting their findings to the 2nd Alzheimer’s Association International Conference on Prevention of Dementia in Washington, DC yesterday. The conference brings together over 1,000 dementia experts from around the world.

The four drugs are an anti-amyloid (Alzhemed), an inhibitor of brain cell death (Dimebon), an “Alzheimer’s vaccine” (Immunotherapy Treatment AN1792), and a drug normally used to treat diabetes (Avandia).

Alzheimer’s disease is thought to be caused by build up of a protein called amyloid beta which forms plaques and tangles in the brain, kills off brain cells and interferes with neuron to neuron signalling.

Approved treatments for Alzheimer’s currently only relieve symptoms for a couple of years and make little impact on the amyloid beta build up and the progress of the disease. Vice president for Medical and Scientific Relations at the Alzheimer’s Association, Dr William Thies said that:

“Amyloid as a cause for Alzheimer’s and a primary target for therapies and preventions must be thoroughly tested.”

“We need an answer to this question so that we can then sharpen our focus on attacking amyloid and creating better treatments, or change the focus to other areas if the theory is wrong,” he added.

Dr Sam Gandy, chair of the Alzheimer’s Association’s Medical and Scientific Advisory Council said they were very pleased to see so many drugs make it to clinical trials, and was optimistic that:

“The odds are quite good that we’ll have more effective new treatments for Alzheimer’s in the near future.”

Developing a new drug is a lengthy and expensive process that takes up to 15 years and on average costs 800 million US dollars. According to the Alzheimer’s Association, only 5 out of 10,000 compounds investigated make it to clinical trials, and of those, only one makes it through to approval for treatment. And, in the case of Alzheimer’s, there are added challenges; for example, the only definitive diagnosis at the moment involves sampling brain tissue.

Anti-Amyloid: Alzhemed

Tramiprosate, brand name Alzhemed (made by Neurochem) is an orally-administered amyloid beta antagonist that is currently in Phase III clinical trials to assess its safety, efficacy and disease modifying effects in patients with mild to moderate Alzheimer’s.

Alzhemed binds to amyloid beta protein and interferes with its ability to build plaque and poison brain cells.

Dr Paul Aisen, Professor of Neurology and Medicine, and Director of the Memory Disorders Program at the Georgetown University Medical Center, Washington DC , and lead author presented the conference with an update of the trial.

The key points were:

  • The randomized, double-blind, placebo controlled trial enrolled 1,052 patients from several medical centres in the US and Canada.
  • All patients were taking doses of acetylcholinesterase inhibitors, with or without memantine.
  • Patients took either the active drug or a placebo twice a day for 18 months and were assessed every three months.
  • Assessments included tests of cognitive function, disability, clinical efficacy, and volumetric MRI to assess effect of the disease on brain volume.

Unfortunately Aisen was unable to present any conclusions because there is a lot of complex data that is still being processed. Apparently there are significant unexpected differences in the data coming from the various sites and these need to be accounted for before the results can be finalized.

Gandy said that while the results of the Alzhemed Phase III clinical trial were not available, there was a positive note:

“We have learned important lessons about how to do these types of very complex, long-term, large-scale Alzheimer’s trials, which in itself is very important because there are now so many promising Alzheimer’s therapies in the pipeline,” he explained.

Brain Cell Death Inhibitor: Dimebon

Dimebon (made by Medivation) is an orally-administered drug that has shown ability to stop brain cell death in preclinical testing for Alzheimer’s and Huntington’s.

Dimebon appears to offer brain cells protection from amyloid build up by blocking something that targets their mitochondria. Mitochondria supply cells with energy and are also involved in programmed cell death (apoptosis) which is associated with neurodegenerative diseases like Alzheimer’s and ageing.

Dr Rachel Doody, Effie Marie Cain Chair in Alzheimer’s Disease Research and Professor of Neurology at Baylor College of Medicine, Houston, Texas reported the 12 month results of a small trial, which was already reported at the six-month stage:

  • The trial took place in Russia and enrolled 183 patients with mild to moderate Alzheimer’s.
  • The patients were randomized to receive Dimebon or placebo three times a day for six months.
  • They were then offered to continue in a double blind trial extension for another six months.
  • No other anti-dementia medication was allowed.
  • Assessments included a battery of cognitive and other tests of behaviour and daily functioning (ADAS-cog was the primary endpoint) performed at baseline and then roughly every 3 months.
  • The results showed that patients improved significantly compared to baseline on all measures and the drug was well tolerated.

According to Dr William Thies, vice president of medical and scientific affairs at the Alzheimer’s Association, Dimebon limits symptoms in a similar way to glutamate antagonists (also used to treat Alzheimer’s) and anticholinesterases such as Aricept.

Adverse events included dry mouth and sweating and over 30 per cent of the patients dropped out of the trial. This high drop out rate could raise some concerns, said some critics, although the results are promising.

Medivation will be seeking approval for Dimebon in 2010.

“Alzheimer’s Vaccine”: Immunotherapy Treatment AN1792

AN1792 is a synthetic form of the amyloid beta protein (made by Elan and Wyeth) which was used in an immunotherapeutic clinical trial that was stopped because 6 per cent of the patients began to suffer from inflammation of the brain (encephalitis).

However, the researchers followed the patients after the trial.

Dr Michael Grundman, Senior Director of Clinical Development in the Alzheimer’s Disease Program at Elan Pharmaceuticals presented their findings to the conference. These showed that 4.5 years after immunization with AN1792, patients who had developed antibodies to amyloid beta continued to show detectable levels of antibodies and slower decline in daily living compared with patients treated with placebo.

The key points of their findings were:

  • 159 patient/caregiver pairs took part in the follow-up (30 placebo patients and 129 patients on AN1792).
  • Of the 129 AN1792 patients, 25 were classed “antibody responders”.
  • Compared to the placebo group, the antibody responders showed significant favourable results in: ability to look after themselves and pursue leisure activities; dependency on caregivers; and memory and thinking skills.
  • After the first year, brain volume changes in antibody responders and placebo patients were similar.
  • No further cases of encephalitis were observed.

“The favorable results on Activities of Daily Living among the antibody responders in this study support the hypothesis that amyloid beta immunotherapy may have long-term benefits for patients with mild to moderate Alzheimer’s and their caregivers,” said Grundman.

Diabetes drug: Avandia

Rosiglitazone, brand name Avandia (made by GlaxoSmithKline) is already approved for treatment of type 2 diabetes (but not for Alzheimer’s). It lowers blood sugar by helping cells use insulin more effectively.

Scientists have speculated that Avandia may also be able to help Alzheimer’s patients because of its effect on brain inflammation and other processes associated with neurodegenerative diseases.

However, in recent months, Avandia has been in the spotlight because a recent study that reviewed the available published research suggested that diabetes patients on Avandia were at increased risk of heart attack and death from cardiovascular causes.

Researchers studied the effect of an extended release form of Avandia (Rosiglitazone XR) on Alzheimer’s patients for 12 months. This was a follow up open lable extension to a randomized controlled trial.

The results suggested that Avandia may help some Alzheimer’s patients depending on their genetic make up. Patients that were “APOE e4 negative” did benefit from the treatment, they showed some improvement. But patients who were “APOE e4 positive” either did not improve or continued to decline.

The key points of the study were:

  • 337 patients with mild to moderate Alzheimer’s enrolled in the study and 82 per cent of them completed it.
  • 7 per cent pulled out because of adverse events.
  • 48 per cent had one or more adverse events (mostly peripheral oedema, or fluid accumulation, in the legs or sacral region, nasopharyngitis or inflammatioon of the nasal passages and pharynx).
  • 9 per cent had one or more severe adverse events, each of which occurred in 1 per cent or less of the patients (except for fractures, 2 per cent).
  • Few patients had clinically significant changes in heart rate (less than 1 per cent) or abnormal ECG readings (2 per cent).
  • Insulin and glycemic control measures were within the range expected for older people with low insulin resistance.

Although there is controversy surrounding the use of Avandia as a type 2 diabetes drug because of the link with elevated heart problem risks, these risks could be outweighed by the potential benefits when considering the benefit-risk profile of person with Alzheimer’s.

Global Clinical Vice President, Neurology, at GlaxoSmithKline, Dr Michael Gold said that Avandia appeared to have a safety profile similar to that already seen in diabetes type 2 patients. He added that:

“Rosiglitazone XR (Avandia) appeared to be generally well tolerated in subjects with Alzheimer’s for up to 72 weeks.”

Thies said: “There is value in continuing to study rosiglitazone in Alzheimer’s. We need to attack the disease through multiple mechanisms, and the only way we can learn with certainty about issues of safety and efficacy in Alzheimer’s is through clinical trials.”

“There are risks involved in clinical studies, and we do need to ensure that all risks are thoroughly described and explained to study participants and family members. That’s why we have informed consent, and why the process is so important,” he added.

Click here for the Alzheimer’s Association (US).

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Written by: Catharine Paddock
Writer: Medical News Today