There is no scientific proof that patients with moderate or severe Alzheimer’s disease benefit from drugs containing the agent memantine. This is the conclusion in the final report that the Institute for Quality and Efficiency in Health Care (IQWiG) published in September 2009.
The report is part of a broader commission awarded by the Federal Joint Committee (G-BA) to assess both drug and non-drug therapy options for Alzheimer’s disease. In addition to memantine, IQWiG has investigated cholinesterase inhibitors, Ginkgo biloba and non-drug therapy alternatives.
Memantine is intended to regulate excess glutamate
Memantine is approved for moderate to severe Alzheimer’s disease, but not for the mild stage of the disease. In Germany memantine is sold under the tradenames “Axura” (Merz) and “Ebixa” (Lundbeck).
Memantine is intended to prevent an excess of glutamate from damaging the brain. Glutamate is a neurotransmitter, in other words a substance that transmits neural signals. Animal experiments have shown that patients suffering from Alzheimer’s disease might have a permanent excess of glutamate, which leads to neural cells dying. Memantine is intended to prevent this without affecting the normal transmission of neural signals.
The substance was developed several decades ago and prescribed for other diseases such as Parkinson’s. Memantine has been used in the treatment of Alzheimer’s disease since 2002.
Studies with nearly 2000 participants included in the assessment
The scientists searched for studies which investigated outcomes that were relevant to patients and their families: this includes cognitive function (e.g. memory capacity) and activities of daily living (e.g. personal hygiene) as well as mental concomitant symptoms (e.g. depression, agitation), quality of life and avoiding being put in a nursing home.
IQWiG was able to include in its assessment 7 studies, in which a total of 1913 patients suffering from Alzheimer’s disease were treated with memantine over a period of 16 to 28 weeks. In 5 of these studies, the subjects received only memantine (monotherapy), in the remaining 2 the substance was administered as an add-on to an existing therapy with a cholinesterase inhibitor. Each study had a comparator control group, in which the patients took a placebo. Up till now, there have not been any usable studies comparing memantine with another dementia drug or with a non-drug therapy.
There are 2 other relevant manufacturer’s studies, but they could not be included in the assessment as not all the necessary data were made available.
Only minimal differences in cognition and activities of daily living
Point scales were used in order to measure activities of daily living and cognitive function. The values were determined on each scale, for example, by giving the patients observation tests or asking the patients and their families about changes in the disease symptoms and how they managed with activities of daily living. However, not every change on such a scale means that the patient’s disease stage actually improves or deteriorates. As the analysis of the study results shows, there are differences between the groups for these 2 outcomes, but these are minimal. Moreover, they are debatable due to the incompleteness of the data. It is therefore doubtful whether patients and their families can in fact see these differences as an advantage.
However, the manufacturer could also have provided evidence of benefit by means of a responder analysis. This investigates whether more patients in the memantine group notice a perceptible improvement in their symptoms than in the placebo group. However, the manufacturer did not provide a reliable responder analysis. Consequently, IQWiG did not find any overall proof of benefit from memantine in the activities of daily living and in cognitive function.
No reliable data on quality of life and necessity of inpatient care
The included studies did not provide reliable information on all outcomes. There are no data on the health-related quality of life of patients because they were not collected in the studies. However, there have been very few suitable instruments for displaying quality of life with this disease.
Although some studies did record whether patients had to be institutionalized, the results are not reliable. Consequently, it remains unclear whether memantine has an influence on how long persons with dementia can be cared for at home.
Data on concomitant symptoms do not reveal any differences
Information on concomitant psychopathological symptoms, such as depression, sleep disorders or severe agitation, was collected and reported. However, the studies do not document any difference between those patients treated with memantine and those given a placebo.
Nor did the scientists find a difference with regard to mortality. However, there is not much information on this as the studies were not designed to address this research question.
Memantine does not have any noticeable drug risks
Participants in the memantine group did not withdraw from the trial on account of adverse effects any more frequently than those in the placebo group. Nor was there any difference in the number of patients with (severe) adverse effects. Thus, there were no noticeable drug risks associated with memantine. However, the longest study only ran for 28 weeks, so it is not possible to draw conclusions on long-term effects. In addition, the number of subjects was altogether too low for potential rare side effects to be recorded.
Other family members do not appear to benefit either
IQWiG did not only consider the patients but also their families. However, the study results did not provide any proof that taking memantine reduces their burden, for instance, by lessening the amount of care required or the emotional burden. None of the included studies defined quality of life of the family caregivers as an outcome. The amount of care required was collected in most of the studies, but the majority of the data was not made available by the manufacturers. Consequently, the present results cannot be reliably interpreted.
Final report takes account of additional, previously unpublished data
IQWiG and its external experts had considerably more data available for the final report than for the preliminary report, in which only 4 studies with a total of 1263 patients could be included. In the course of the submission of comments procedure, the manufacturers submitted previously unpublished study analyses. For the final report, Merz provided subgroup analyses of participants with moderate and severe Alzheimer’s disease because in some studies memantine had also been given to patients with mild severity, which was not in compliance with approval when viewed from today’s perspective.
Nevertheless, the data pool for the final report is still incomplete. Relevant information is still lacking on 2 more clinical trials with a total of 580 participants. In contrast to the preliminary report, IQWiG has not placed a caveat on the final report because the small amount of information published on these 2 studies, including that disseminated at conferences, suggests that the minimal effects on cognition and activities of daily living would be even less if the missing data were included. There would be no change to the overall result – the lack of proof of benefit.
More research is needed
According to the scientists, the study pool for memantine is still insufficient overall. There is a lack of studies of longer duration that enable the long-term effects of therapy with memantine to be estimated. There is also a lack of research on patients living in nursing homes who suffer from the concomitant diseases typical in this age group. It cannot be excluded that memantine has a better effect in some patient groups.
“As long as it is not proven that therapies give patients or caregivers a perceptible advantage, it is very difficult to justify continuing to prescribe them when their costs are carried by the general public,” comments Peter Sawicki, Director of IQWiG. “The number of elderly people is growing and so are the medical and social problems associated with Alzheimer’s disease. I don’t think that we will find a simple solution to this problem in the near future. That’s why it is important at this stage to provide better social and medical care to patients and to relieve the burden for family caregivers. And it is surely better to ‘invest’ in this rather than in drugs, where we don’t know whether they actually provide a benefit.”
Source: Dr. Anna-Sabine Ernst
Institute for Quality and Efficiency in Health Care
The COX-2 inhibitor Bextra, which Pfizer… suspended from the U.S. market in April citing safety concerns, might return to the market, Pfizer CEO and Chair Hank McKinnell said in an interview with USA Today reporter Julie Appleby published Friday. In the interview, McKinnell also discussed prescription drug prices, pharmaceutical advertising and FDA regulation. Speaking about Bextra, McKinnell said, “I do know for many people it is the best option. … We think with the appropriate safety program in place, there is a possibility it could be returned to market.” McKinnell suggested that players “reframe” the health care system to focus on consumer health, education and disease prevention. In addition, McKinnell said that under the health care system’s present structure, “large employers provide health care apparently free of charge to employees.” McKinnell said, “Employees have the mistaken belief that someone else pays the bill. We need to make individuals more responsible for their own health care.” He added that reducing mortality rates from cancer and heart disease by 10% would generate $10 trillion in savings through greater productivity and lower costs. McKinnell recommended that the U.S. government implement trade agreements that require foreign governments pay a “fair share” of drug research and development costs to “end the free ride” that other nations receive for U.S.-manufactured prescription drugs. McKinnell said he believes that the United States has the “safest drug supply in the world,” but he added that the public must understand that “there is no such thing as an absolutely safe medicine” and that any drug “powerful enough to do good can also do some harm.” McKinnell said the drug industry should be required to submit advertisements to FDA before they run. He added that voluntary regulation of drugs that are already on the market is “probably not good enough” and that safety and monitoring efforts should be linked to large databases (Appleby, USA Today, 5/20).
“Reprinted with permission from kaisernetwork kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.
View drug information on Bextra.
While a good belly laugh is widely recognised for its health benefits, new findings* confirm laughter can be a serious matter for over a third of Australians with asthma (39%), acting as a trigger for their condition.
In Australia, asthma is one of the most widespread chronic health problems, affecting over two million Australians.1 A more serious concern from this research* is that most people with asthma live with the false belief that their asthma is well managed (74%) even though the majority of this group are missing out on the good things in life – anything from laughing, socialising and exercising to getting a good night’s sleep (85%).
Experts are urging people with asthma to stop accepting lifestyle restrictions as part and parcel of asthma, as better management can help them get the most out of life every day. For the first time, people with asthma can find out what they are missing with the launch of the Asthma Life Balance Check, a fast and easy online assessment tool which aims to give insight into how they are living their life and how well they are managing their condition.
“When asthma is managed well, people should be able to enjoy life’s every day pleasures which most of us take for granted,” explains Professor Christine Jenkins, thoracic physician from Concord Hospital in Sydney. “Worryingly, these findings show that whilst many believe they have their asthma under control, asthma is actually controlling them and their lifestyles.”
The research* also found almost half of those surveyed struggle to do their favourite activities (49%) and almost two thirds find themselves breathless with everyday activities such as housework and shopping (63%). Well over a third feels tired because of disturbed sleep (43%) and a fifth cancels social engagements because of their asthma (20%).
Furthermore, 22 per cent of all those surveyed admitted to having an ‘asthma attack’ and 15 per cent had to take time off work or study in July.*
Dr Noela Whitby AM, National Asthma Council Australia Chairman, hopes the
– Asthma is a disease of the airways in the lungs that causes inflammation (redness) and swelling. Asthma symptoms include wheezing, coughing (particularly at night), chest tightness, difficulty in breathing and shortness of breath.1
– The prevalence of asthma in Australia is relatively high, by international standards.1
– In Australia, asthma is one of the most widespread chronic (long-term and persistent) health problems. It affects over two million Australians, and is more common in women than in men.1
– People with asthma report poorer general health and quality of life than people without asthma.1
– Poorly controlled asthma restricts participation in normal physical and social activities.2
– With appropriate treatment and a personal commitment to good self-management, most people with asthma can lead normal, active lives.3
– An Australian study performed at the University of New South Wales showed that laughter is an asthma trigger for over 40 per cent of Australians with asthma.4 A similar study carried out at New York University showed that laughter is a common asthma trigger for over 50 per cent of the subjects tested.5
Biotechnology company Arana Therapeutics Limited (ASX: AAH, AIM: AAHx) announced plans for the next stages of clinical development for ART621 – its lead anti-TNF domain-based antibody.
Following successful completion of a Phase I study of ART621, Arana now plans to conduct a 3-month Phase IIa dose-finding study in psoriasis patients ahead of a Phase II study in rheumatoid arthritis.
The psoriasis study, to be conducted in Australia, is expected to commence in Q1/2008 and the Phase II rheumatoid arthritis program is planned to start in Q3/2008.
Arana has also completed pharmacokinetic analysis of data from the Phase I trial of ART621. The data indicate that ART621 has a half life of approximately 14 days in volunteers following subcutaneous administration. These data suggest that, although ART621 is approximately half the size of conventional antibodies, it remains in the blood stream for at least as long as currently marketed anti-TNF antibody products.
A summary of the data from the Phase I study will be presented at the IBC Antibody Therapeutics Conference in San Diego on 5th December.
CEO John Chiplin commented “We are delighted that we have been able to successfully engineer the novel domain construct into a product that has properties in line with the leading marketed products. The indicative half life of ART621 appears to be competitive with the current marketed product Humira® and greater than Remicade® and Enbrel®.”
“We look forward to learning from our clinical trials if the smaller molecular weight of ART621 translates into important clinical benefits in the treatment of inflammatory diseases.”
“The inflammatory disease market continues to grow and the interest in and potential importance of ART621 is reflected by the invitation to present our data at the prestigious IBC Antibody conference,” Chiplin added.
Commenting on the clinical development plans Dr Chiplin said “The favourable half life of ART621 has opened up opportunities in improved dosing for patient benefit. The psoriasis trial will allow us to quickly obtain safety, efficacy and repeat dose pharmacokinetic data to better inform the design of our Phase II rheumatoid arthritis program. “
“Such an approach has been used successfully by other companies and should help speed the development of our TNF product. Furthermore, psoriasis is a valuable market in its own right and contributes to the major markets enjoyed by the currently marketed products,” Chiplin added.
About Arana Therapeutics
Arana Therapeutics (ASX: AAH; AIM: AAHx) is an international biopharmaceutical company formed through the merger of Peptech and EvoGenix in August 2007. The company uses superior technology to develop next generation drugs that will improve the lives of patients with inflammatory diseases and cancer.
Arana Therapeutics’ innovative engineering technologies provide the basis for clinical development in the antibody space, a market which draws on high demand. With a market capitalisation of around A$250 million and solid cash resources, Arana Therapeutics has the financial stability and management expertise to accelerate its clinical programs, and is on track to have at least 3 clinical stage assets within three years.
Arana is listed on the Australian Securities Exchange (ASX) and the London Stock Exchange (AIM).
The pipeline consists of four lead drug programs: ART621 to treat severe rheumatoid arthritis and other inflammatory diseases; ART010 to treat osteoporosis and bone cancer; ART104 to treat solid tumours in colorectal cancer; and ART150 for lung cancer and melanoma. Additionally, the company has earlier stage products in development for the treatment of a range of conditions including age related macular degeneration, psoriasis, colorectal cancer, and leukaemia.
Arana has recurring revenues from commercial and development partnerships with six international companies including GSK, CSL, Centocor (J&J) and Abbott Laboratories
Arana Therapeutics Limited
View drug information on Enbrel; Humira; Remicade.
Researchers from the German Centre for Neurodegenerative Diseases (DZNE) and the Ludwig-Maximilians-Universit?¤t (LMU) in Munich have shown that the ADAM10 protein can inhibit the formation of beta-amyloid, which is responsible for Alzheimer’s disease. ADAM10 acts like a pair of molecular scissors to cut the protein from which beta-amyloid is formed, effectively preventing the formation of beta-amyloid. This makes ADAM10 a key molecule in Alzheimer’s therapy.
The research team has just published detailed information on their findings in the online edition of the EMBO Journal. The brains of Alzheimer patients have high accumulations of the material beta-amyloid, which appear in the form of plaques. The precursors of these plaques are believed to be the underlying cause of the nerve cell loss that leads to the disruptions in memory that characterize Alzheimer’s disease. The main aim of many Alzheimer therapies is therefore to inhibit the formation of beta-amyloid. Since beta-amyloid is cleaved from the so-called amyloid precursor protein (APP), scientists have focused on stopping the two enzymes that attack the precursor protein. These act like molecular scissors and cut out the beta-amyloid fragment. Blocking these scissors precludes the formation of beta-amyloid. DZNE and LMU researchers have succeeded in identifying an enzyme known as alpha secretase, which cleaves the amyloid precursor protein (APP) without forming beta-amyloid. Up to this point three different candidates for this function had been under consideration, but the research team has now been able to show that the enzyme ADAM10 alone is responsible for the specific cleavage.
Dr. Stefan Lichtenthaler and his team developed highly specific antibodies that can identify the different cleavage products of the precursor protein in the brain cells of mice and in human cell cultures. Using a special technique called RNA interference, the researchers managed to block each of the three genes that code for the three ADAM enzymes under suspicion. An analysis of the cleavage products revealed that the ADAM10 gene was the only one able to prevent the formation of beta-amyloids. They confirmed their results using mass spectrometry. “In ADAM10 we have identified a target molecule that plays a central role in the development of the molecular processes in Alzheimer’s disease. We know that ADAM10 is less active in Alzheimer patients,” says Dr. Lichtenthaler. When ADAM10 is less active, the precursor protein is more likely to be cleaved in a way that promotes the formation of beta-amyloids.
“It is possible that less ADAM10 activity could increase susceptibility to Alzheimer’s disease. If that is the case, stimulating ADAM10 could be an important mechanism for therapy. But our antibodies also open up new possibilities for diagnosing and preventing the disease,” says Lichtenthaler. The antibodies could be used to measure ADAM10 activity in spinal fluid and, by extension, identify persons who may have an increased risk of developing Alzheimer’s disease. A series of experiments to examine this possibility is already underway.
Source: Ludwig-Maximilians-Universitaet Muenchen (LMU)
Arthritis Care, the UK’s largest support charity for people with arthritis, welcomes the National Audit Office report into rheumatoid arthritis services and urges health chiefs to implement its recommendations as swiftly as possible.
The audit highlights ‘minimal’ GP training in rheumatoid arthritis (RA) and poorly co-ordinated services, which the charity says means thousands of people with this devastating disease are failed by the system.
‘The NAO report echoes what people with RA have been telling Arthritis Care for years – that it takes too long to get diagnosed. Early diagnosis and referral for suitable treatment is crucial as it can literally stop this debilitating condition in its tracks. We applaud the audit’s recommendations that the Department of Health and Primary Care Trusts (PCTs) replace their often scattergun delivery with joined-up services. If actioned, the recommendations in this report should dramatically improve life for people with RA as well as save the country millions of pounds’, said Neil Betteridge, Arthritis Care’s chief executive.
44 year-old Elizabeth Ogg from West Sussex developed rheumatoid arthritis 6 years ago after the birth of her son. Elizabeth, who used to work as a management consultant, said: “It was terrifying when I started getting unbearable pains in my arms and legs. My mother urged me to see my doctor straight away – my father had RA and she recognised the potential symptoms immediately. Even with the private health care I had through my job, it still took over 6 months to get the correct diagnosis and start treatment.’
‘After I was diagnosed, it became very clear that my GP at the time had very little understanding of RA, how severe it was or the medication that I would need to use. I didn’t have any guidance or support and I was never referred to any specialist services, not even a physiotherapist – it was a disaster. Thankfully, I recently moved to West Sussex and since then I cannot praise the support I’ve had enough. My GP is wonderful – she has a special interest in rheumatology and I see a specialist nurse regularly as well as a physiotherapist and podiatrist. I’m finally getting the support I need to live with my condition. I can’t believe the difference in service I’ve experienced – it just shouldn’t be this way.”
Arthritis Care believes that the key to addressing the majority of the problems identified by the NAO lies in the proper implementation of the Department of Health’s Musculoskeletal Services Framework. The framework, launched in 2006 is a strategy for the delivery of integrated musculoskeletal services for England.
‘The Musculoskeletal Services Framework was devised to improve services but any implementation has been intermittent and half-hearted. As the audit says, 73% of PCTs have not even undertaken any assessment to establish the number of people with RA in their areas. Arthritis Care is calling on the government and Strategic Health Authorities, plus every PCT, to respond to the audit by prioritising proper implementation of the framework. We also want to see a National Clinical Director for musculoskeletal services appointed to drive through improvements in services, just in the same way as one exists in the areas of mental health, diabetes and heart disease’, says Betteridge.
Adding tadalafil (Cialis®; Adcirca®) to the treatment of people with scleroderma can improve Raynaud’s phenomenon symptoms and heal and prevent hand and finger ulcers associated with it, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta.
Scleroderma (more formally called systemic sclerosis) is a rheumatic disease that results in the thickening and tightening of skin, as well as a build-up of scar tissue and damage to internal organs. Scleroderma is a relatively uncommon problem, affecting only 200 to 300 people per million in the U.S. Some 12 to 20 new cases per million are diagnosed annually. Effective treatments are available for some forms of the disease, although scleroderma is not yet curable. The majority of patients with scleroderma also suffer from Raynaud’s phenomenon structural damage of the blood vessels that cause them to react abnormally to the cold. Raynaud’s phenomenon is commonly marked by discoloration of the hands, fingers and toes. This occurs due to poor blood flow and, in severe cases, can lead to damage such as finger ulcers, gangrene and scarring. These problems may adversely affect the functioning of the hands and quality of life during winter months.
Researchers recently completed a study to evaluate the effectiveness of adding tadalafil, a drug that can increase arterial blood flow and is commonly used to treat erectile dysfunction, to treat Raynaud’s phenomenon in people with scleroderma. They studied 53 patients of which 50 were women whose average age was almost 37 years and who had suffered from scleroderma, on average, for almost six years. Twenty-six of the participants had limited scleroderma (which only occurs in the forearms, hands, legs, feet and face) and 27 had diffuse scleroderma (which can affect almost any area of the body). All participants met the American College of Rheumatology’s criteria for scleroderma diagnosis and had at least four Raynaud’s attacks per week.
The participants were monitored for one week to determine the initial severity of their disease and then were placed into two groups. The first group, of 26 participants, received placebo to take every-other-day in addition to their usual vasodilators (medication used to relax and widen blood vessels). The second group, of 27 participants, was given 20mg of tadalafil to take every-other-day in addition to their existing vasodilators. Participants in both groups did not know what treatment they were receiving and followed their treatment assignment for eight weeks.
Researchers then monitored the progress of each participant. They noted the number of daily Raynaud’s attacks and other measures of Raynaud’s, including the length of each individual attack, healing of existing hand and finger ulcers, appearance of new finger ulcers and improvement in scleroderma symptoms based on health and quality of life assessment questionnaires.
Researchers noticed that improvement in the tadalafil group was significantly better than in the placebo group. At the beginning of the study, 18 patients in the tadalafil group had ulcers as compared to 13 patients in the placebo group. Following treatment with tadalafil, 14 out of 18 of those patients healed completely as compared to five out of 13 patients in the placebo group. Further results revealed that new ulcers appeared in only one patient in the tadalafil group as compared to nine patients in the placebo group. Additionally, other symptoms such as dyspnea (difficulty breathing), Raynaud’s phenomenon and digital ulcers were greatly improved in those taking tadalafil. Finally, researchers noted that side effects were similar in both groups and no serious side effects were observed.
These results led researchers to believe that adding tadalafil to existing Raynaud’s phenomenon therapy may be of great benefit to people with scleroderma.
“Tadalafil, in combination with other vasodilators, not only improves the number, duration and severity of Raynaud’s attacks, but also heals the existing digital ulcers as compared to placebo,” explains Vikas Agarwal, MD; associate professor of clinical immunology at the Sanjay Gandhi Postgraduate Institute of Medical Sciences and lead investigator in the study. “In addition to preventing the development of new digital ulcers, tadalafil in combination with other vasodilators marks the beginning of new phase of oral therapeutic options available for severe scleroderma.”
Patients should talk to their rheumatologists to determine their best course of treatment.
Source: American College of Rheumatology (ACR)
View drug information on Adcirca; Cialis.