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Cerebrolysin A Unique Treatment Option for Alzheimers Disease


a report by

EBEWE Pharma

Introduction

about 50% of all nursing home placements are due to dementia.


Care of Demented Patients

Currently, there are an estimated 18 million people in the world with dementia. Of these, 12 million two-thirds live in developing countries. By 2025, the number of people with dementia will have nearly doubled and it is estimated that just over 24 million (>70%) of these will live in developing countries. Much of this increase will be in rapidly developing and heavily populated regions such as China, India and Latin America. Alzheimers disease (AD) is a progressive neurodegenerative disorder and is one of most prevalent diseases of the elderly. In the classification of dementias, AD accounts for more than 60% of all dementias, while vascular dementia is the second leading cause, accounting for an estimated 5% to 20% of cases.1 In Japan, vascular dementia is felt to be the most common cause of dementia, accounting for ~50% of all dementia cases. Multiple different aetiologies of dementia may co-exist. Indeed, macro- or micro-cerebrovascular disease can further exacerbate an existing cognitive impairment due to AD. An example of this is Germany. Assuming a mean prevalence of 6% to 8%, the number of demented persons in Germany lies between 770,000 and 1.2 million. About 25% of these patients are aged between 65 and 69 years, about 60% between 80 and 89 years and about 10% are over 90 years of age. Given the expected increase in the number of elderly individuals among the German population, which has been estimated at an additional four million within the next 50 years, one must anticipate that there will be between 1.1 and 1.6 million demented persons in Germany by 2050.2 The survival period with dementia after the onset of dementia symptoms decreases with the patients age,3 with an average life expectancy of 4.3 years in women and 3.3 years in men.4 Dementia is one of the most common causes for functional dependency and accounts for the largest proportion of disability in the elderly population. Several studies have shown that about 90% of moderately and severely demented individuals require permanent nursing home care5,6 and that
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Several representative cross-sectional studies in the population segment over 65 years of age in Germany reported a total prevalence of 7% in need of permanent nursing care.79 The percentage of demented persons can actually only be estimated, but existing studies indicate that 50% to 70% of elderly persons who are in need of care have dementia.10,11 In the highest category, i.e. in patients who are physical dependent on care, 80% are demented. About 50% of all nursing home placements are due to dementia.1215 In industrialised countries, there is a trend towards less family care and more institutionalised care due to several disease-imminent factors and demographic changes. During the course of their illness, between two-thirds and three-quarters of all demented patients are placed in nursing homes.9,16 Crosssectional surveys show that at least 40% of all demented patients are being cared for in nursing homes, with a mean duration of institutionalisation ranging from 2.6 to 3.1 years.1619 The burden on the family members of the demented patients, usually spouses or daughters, is extremely high. Future availability of such family care-giver support is threatened by greater inter-generational independence as, in the future, an ever-increasing number of elderly people will be living alone without a younger relative nearby. Already more than 40% of the elderly in Germany are currently living alone. In the developed world, people with dementia live mainly on their own, or only with their spouse who also is elderly. In developing countries, people with dementia mainly live in large extended family units, but this is changing rapidly. Currently, 50% of all people with dementia live with at least four other persons. 25% or more (50% in India) live in a three-generation household with children under the age of 16. Persons

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with dementia still retain their senior status in the family. More than half in India and Nigeria are still regarded as the head of the household. With the mean duration of daily homecare ranging between six and 12 hours and approximately 50% of the care taking place at night, up to 40% of all caregivers fall ill themselves, frequently with depression, anxiety disorders or psychosomatic symptoms.20 Studies show that carers stress is mainly due to behavioural disturbances of the patients, including aggressive behaviour, and has no significant relationship to cognitive impairment.17 Therefore, most nursing home placements are due to severe behavioural changes such as agitation and aggression or severe impairments in physical function, such as incontinence. Both structured and informal social support groups and intervention programmes tend to reduce the psychological stress of the care-givers and their morbidity; they also tend to delay institutional placement.2022
The Economic Impact of Dementia

People with dementia are heavy users of healthcare/ social services. The costs amount to a substantial proportion of the average wage for a specific country. This is particularly the case for the poorer regions, e.g. India, China and Nigeria. A cost analysis of dementia in Germany is still in an early phase. Most research in terms of the economic impact of dementia has been conducted in the US and the UK.14,15,23 One US investigation estimated the total cost for dementia at US$67.3 billion, with yearly total costs amounting to approximately US$48.000 per patient.14 Assuming a prevalence of 800,000 to 1.2 million demented persons in Germany, the total costs range between 35 and 56 billion per year, with total costs per year per demented patient totalling approximately 50,000. All studies agree that the indirect costs of dementia are 1.4 to 2.3-fold higher than the direct costs and account for up to 70% of total costs.23,24 Between 50% to 70% of indirect costs are the result of family care, while 55% to 75% of direct costs are due to long-term residential care of demented patients.15 Costs increase with the severity of illness, due to more frequent use of institutionalisation, short-term hospitalisation and the daily hours care-givers spend on caring.23
Cerebrolysin A Unique Neurotrophic Treatment Option

There are direct and indirect costs associated with dementia. Direct costs include diagnosis, in-patient and out-patient treatment, skilled nursing facility care and residential long-term care. Indirect costs mainly include the losses of the family, such as loss of productive time of the care-giver, loss of lifetime earnings owing to disability and premature mortality. The economic impacts can be judged in terms of lost income and higher costs.
Lost Income

In the developing world, dementia can be an even more difficult burden for the families of the patients, as some studies have demonstrated. A substantial proportion of care-givers have to reduce their paid work or even to stop work altogether in order to care for the person with dementia. Care sometimes is also provided by other family members or by friends and neighbours in the local community. Some of these care-givers also have to cut back on their paid work. Fewer than 20% of people with dementia in India and Nigeria, and around half in China and Latin America, receive any retirement payments. Fewer than 5% of the people with dementia receive any disability benefits.
Higher Costs

At present, treatment of AD is largely restricted to symptomatic interventions. The main therapeutic approach to AD has been cholinergic transmitter replacement, which led to the development of cholinesterase inhibitors. Their overall efficacy, however, has been modest at best and they provide only symptomatic benefit.25. Thus, stabilising strategies aiming at delaying disease progression are being investigated.26 Among others, treatment with neurotrophic agents is a promising alternative, with the potential to modify the course of AD and delay its progression. Among other lines of research, neurotrophic factor therapy has long been recognised as a promising treatment approach for AD. Experimental studies have demonstrated that specific neurotrophic factors play a key role in maintaining cholinergic, noradrenergic and serotonergic neurons, cell populations that undergo progressive degeneration in AD.27 Therefore, neurotrophic factors or molecules that mimic the action of these factors potentially modify the course of AD and delay its progression.26 Cerebrolysin is a peptide preparation that has
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Families often employ additional professional caregivers, during the day and also at night. These professional care-givers must be paid.

Cerebrolysin A Unique Treatment Option for Alzheimers Disease


neurotrophic effects in various animal models of AD.28,29 It is produced by a standardised enzymatic breakdown of purified brain proteins and consists of 25% low molecular weight peptides and free amino acids. Cerebrolysin is currently approved and marketed in 36 countries for the treatment of AD. Clinical trials demonstrated the efficacy of Cerebrolysin in the treatment of AD after intravenous (IV) application. The results of recent clinical trials suggest that Cerebrolysin has beyond its symptomatic effect a unique stabilising effect in patients with AD. Cerebrolysin displays neurotrophic and neuroprotective activity in vitro and in vivo. In contrast to nerve growth factors, Cerebrolysin causes this effect after peripheral injection, suggesting that the small molecules are able to penetrate the blood-brain barrier in pharmacodynamically significant amounts. In a model of fimbria-fornix transsection, Cerebrolysin prevented degeneration of medial septal cholinergic neurons and improved lesion-induced cognitive deficits in animals.28 Significant improvements in learning and memory were also achieved in old animals, which were associated with a significant increase in synaptic density in the hippocampus and the entorhinal cortex. In a model of apolipoprotein-E knock-out mice, Cerebrolysin improved the cognitive deficits and exhibited morphological effects, suggesting a normalisation of the impaired neuronal cytoarchitecture.29 In transgenic mice over-expressing amyloid precursor protein, Cerebrolysin reduced A142 load and counteracted behavioural deficits. Cerebrolysin improved spatial orientation learning and memory, and histological examinations of the brains of the animals revealed a significant increase in synaptic density.30 To date, the clinical database for Cerebrolysin encompasses more than 80 clinical trials with over 5,000 patients; the majority of the patients in these clinical trials had dementia, in particular AD. Patients were enrolled into these clinical trials if they were suffering from mild to moderate AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association (NINCDS-ADRDA) or International Classification of Disorders (ICD) criteria, and had Mini Mental State Examination (MMSE) scores of 12 to 26. All patients were treated with IV infusions of 30ml Cerebrolysin (or placebo) five days per week for four weeks, with the exception of two studies in which this regimen was repeated after a treatment-free interval of two months. The clinical follow-up ranged from one month in the earlier studies up to seven months in the more recently completed trials.
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In these clinical trials, the beneficial effects of Cerebrolysin on various domains of AD, including cognitive performance, global function and activities of daily living, have been demonstrated. In the following, the results of recently completed, randomised, placebo-controlled, double-blind clinical trial are summarised and reviewed. The vast majority of the clinical trials with Cerebrolysin in AD to date focused on mild to moderate AD patients with MMSE scores ranging from 12 to 26. One example is the clinical trial by E Ruether and colleagues.31 To evaluate the efficacy of Cerebrolysin in patients with more advanced AD, a subset analysis of patients enrolled in the above-mentioned recently completed clinical trial was performed. This subgroup analysis included patients with moderate to moderately severe AD, with MMSE scores of 19 and below (range: 5 to 19), and was published 2002.32 This was a seven-month, randomised, double-blind, placebo-controlled, parallel-group clinical trial with 149 patients. The clinical trial was conducted in Germany and Austria according to International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (ICH-GCP) guidelines. Written informed consent was provided by the patient and the care-giver. The full details are published as mentioned above. Of the full patient sample, 109 had aN MMSE score of less than 20, and these patients were included in the subset analysis (Cerebrolysin n=60; placebo n=49).
Efficacy

A responder analysis showed that 65% of Cerebrolysin-treated patients responded to therapy, compared with 24.5% of control patients (p<0.001). The treatment effect persisted up to week 28, i.e. three months after the end of the treatment. During this follow-up examination, 48.3% of the Cerebrolysin patients had improvement of global function from baseline, in contrast to only 16.3% of the placebo patients (p=0.005). This indicates that the beneficial effects of Cerebrolysin were maintained for three months after drug withdrawal. Comparable results were observed in the cognitive domain. On the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), a significant effect of Cerebrolysin was observed at week 16, with responder rates of 55% for Cerebrolysin, compared

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with 16.3% for placebo (p=0.001). Patients on Cerebrolysin had an improvement from a baseline of -3.0 points, while placebo patients worsened by 1.1 points, accounting for a treatment difference of -4.1 points in favour of Cerebrolysin (p<0.001). The beneficial effect of Cerebrolysin was maintained until week 28, with a group difference of -2.8 points in favour of Cerebrolysin (p=0.004). Improvement of cognitive function correlated well with improvement of global function. At week 16, 25 of the 60 Cerebrolysin-treated patients (42%) responded in the common gateway interface (CGI) (score < 5) and also showed an improvement of (4 points in the ADAS-cog. This fraction was much lower in the placebo group, with only 10% of the patients meeting both the CGI and ADAS-cog response criteria (p=0.002). The group difference in the CGI score is 0.75 points in favour of Cerebrolysin and is among the highest reported in the medical literature. The results of the secondary outcome measures provided supportive evidence for the efficacy of Cerebrolysin. In the activities of daily living (Nuremberg Activities Inventory (NAI) score), despite not reaching statistical significance, there was a clear trend (p=0.1) in favour of Cerebrolysin with a drug-placebo difference of 0.6 points at week 16. Significant superiority of Cerebrolysin over placebo was evident in the behavioural domain. The treatment difference in the ADAS-noncog at week 16 was -1.3 points in favour of Cerebrolysin (p=0.002). This favourable effect was not only maintained, but it increased after the washout phase. At week 28, patients on Cerebrolysin had improved by -0.2 point, whereas
Figure 1: Time Course of the ADAS-noncog

placebo-treated patients had deteriorated by 1.6 points (p=0.001), accounting for a group difference of 1.8 points in favour of Cerebrolysin (see Figure 1).
Safety

The overall incidence of the adverse effects (AEs) was similar in both treatment groups: 43.4% of the Cerebrolysin patients, compared with 38.0% of the placebo patients, experienced at least one AE. Most AEs were rated mild in both treatment groups. The most common AEs reported by patients on Cerebrolysin were vertigo, headache, sweating and nausea. These AEs, however, occurred with a similar frequency in the placebo group. Cerebrolysin was well tolerated. This clinical trial demonstrates that IV treatment with Cerebrolysin results in statistically and clinically significant improvement of global function, cognitive performance and behavioural performance in patients with moderate to moderately severe AD. The results are in accordance with the data of the full sample, where Cererbolysin was significantly superior to placebo. This subset analysis demonstrated an even slightly higher positive treatment effect in patients with more advanced disease. This data points to a possible disease modifying action and a stabilising effect of Cerebrolysin in AD, which goes far beyond a pure symptomatic effect. This is in agreement with the reported neurotrophic activity of Cerebrolysin. In conclusion, the neurotrophic compound Cerebrolysin leads to statistically significant and clinically relevant improvements of cognitive performance and global function in patients with moderate to moderately severe AD. The therapeutic benefit is maintained in part for at least three months after drug withdrawal, suggesting a stabilising effect of Cerebrolysin in patients with AD. Cerebrolysin fulfils the requirements of a modern therapy for AD; it improves the activities of daily living, which, in turn, makes a postponed time of institutionalisation possible, and which reduces the burden of the care-giver as well as the burden on the healthcare budget.
Contact Information EBEWE Pharma Mondseestrae 11 A-4866 Unterach Austria Tel: (43) 7665 8123 0 Fax: (43) 7665 8123 11 http://www.ebewe.com e-Mail: office@ebewe.com

Mean change from baseline (SEM) of Cerebrolysin-treated and placebo-treated patients. n=60 for Cerebrolysin and n=49 for placebo. Negative score differences indicate improvement.

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Cerebrolysin A Unique Treatment Option for Alzheimers Disease


1. L Fratiglioni, L J Launer, Andersen, et al., Incidence of Dementia and Major Subtypes in Europe: A Collaborative Study of Populationbased Cohorts, Neurology, 54 (2000) Suppl. 5, pp. 1015. 2. H Bickel, Demenzsyndrom und Alzheimer Krankheit: Eine Schtzung des Krankenbestandes und der Jhrlichen Neuerkrankungen in Deutschland, Gesundheitswesen, 62 (2000), pp. 211218. 3. H F A Diesfeld, L R van Houte and R M Moerkens, Duration of Survival in Senile Dementia, Acta Psych. Scan., 73 (1986), pp. 366371. 4. D B Hier, J D Warach, P B Goelick, et al., Predictors of Survival in Clinically Diagnosed Alzheimers Disease and Muliinfarct Dementia, Arch. Neurol., 46 (1989), pp. 1,2131,216. 5. J E Graham, K Rockwood, B L Beattie, et al., Prevalence and Severity of Cognitive Impairment with and without Dementia in an Elderly Population, Lancet, 349 (1997), pp. 1,7931,796. 6. B Cooper, H Bickel and M Schufele, Demenzerkrankungen und Leichtere Kognitive Beeintrchtigungen bei lteren Patienten in der rztlichen Allgemeinpraxis. Ergebnisse einer Querschnittsuntersuchung, Nervenarzt, 63 (1992), pp. 551560. 7. U Schneekloth and U Mller, Hilfeund Pflegebedrftige in Heimen. Schnellbericht zur Reprsentativerhebung im Rahmen des Forschungsprojekts Mglichkeiten und Grenzen Selbsstndiger Lebensfhrung in Einrichtungen, Infratest, 1995. 8. U Schneekloth and P Potthoff, Hilfe und Pflegebedrftige in Privaten Haushalten, Kohlhammer, 1993. 9. H Bickel, Pflegebedrftigkeit im Alter: Ergebnisse einer Populationsbezogenen Retrospektiven Lngsschnittuntersuchung, Gesundheitswesen, 58 (1996) Suppl. 1, pp. 5662. 10. R Harrison, N Savla and K Kafetz, Dementia, Depression and Physical Disability in a London Borough: A Survey of Elderly People in and out of Residential Care and Implications for Further Developments, Age Ageing, 19 (1990), pp. 97103. 11. H Aguerro-Torres, L Fratiglioni, Z Guo, et al., Dementia is the Major Cause of Functional Dependence in the Elderly: 3-year Follow-up Data from a Population-based Study, AJPH 88, 1998, pp. 1,4521,456. 12. H Bickel, Demenzkranke in Alten- und Pflegeheimen: Gegenwrtige Situation und Entwicklungstendenzen, Forschungsinstitut Der Friedrich-Ebert-Stiftung (Hrsg) Alzheimer Krankheit: Der Langsame Zerfall Der Pesrnlichkeit, Bonn: 1995, pp. 4968. 13. P S German, B W Rovner, L C Burton, et al., The Role of Mental Morbidity in the Nursing Home Experience, Gerontologist, 32 (1992), pp. 152158. 14. R L Ernst and J W Hay, The US Economic and Social Costs of Alzheimers Disease Revisted, AJPH 84, 1994, pp. 1,2611,264. 15. T Ostbye and E Crosse, Net Economic Cost of Dementia in Canada, Can. Med. Assoc. J., 151 (1994), pp. 1,4571,464. 16. M A Severson, G E Smith, E G Tangalos, et al., Patterns and Predictors of Institutionalization in Community-based Demented Patients, JAGS, 42 (1994), pp. 181185. 17. R F Coen, Behaviour Disturbance and Other Predictors of Carer Burden in Alzheimers Disease, Int. J. Ger. Psych., 12 (1997), pp. 331336. 18. L E Hebert, P A Scherr, L A Becket, et al., Age-specific Incidence of Alzheimers Disease in a Community Population, JAMA, 273 (1995), pp. 1,3541,359. 19. H G Welch, J S Walsh and E B Larson, The Cost of Institutional Care in Alzheimers Disease: Nursing Home and Hospital Use in a Prospective Cohort, JAGS, 40 (1992) , pp. 221224. 20. R G Morris, L W Morris and P G Britton, Factors Affecting the Emotional Wellbeing of the Carers of Dementia Sufferers, Br. J. Psychiatr., 153 (1988), pp. 147156. 21. H Brodaty and M Gresham, Effects of a Training Program to Reduce Stress in Carers of Patients with Dementia, Brit. Med. J., 299 (1989), pp. 1,3751,379. 22. H Brodaty, M Gresham and G Luscombe, The Prince Henry Hopsital Dementia Care givers Training Programme, Int. J. Ger. Psych., 12 (1997), pp. 183192. 23. E Souetre, R M A Thwaites and H K Yeardly, Economic Impact of Alzheimers Disease in the United Kingdom, Br. J. Psych., 174 (1998), pp. 5155. 24. H Bergmann, Understanding Placement of the Demented Elderly, Adv. Experiences Med. Biol., 282 (1990), pp. 103112. 25. S Gauthier, Acetylcholinesterase Inhibitors in the Treatment of Alzheimers Disease, Exp. Opin. Exp. Drugs, 8 (1999), pp. 1,5111,520. 26. J Gray and S Gauthier, Stabilization Approaches to Alzheimers Disease, Clinical Diagnosis and Management of Alzheimers Disease, (2nd edition) S Gauthier (ed.), Martin Dunitz: 1999, pp. 269278. 27. M E Jnhagen, Nerve Growth Factor Treatment in Dementia, Alzheimers Disease and Associated Disorders, 14 (2000), pp. S31S38. 28. F Akai, S Hiruma, T Sato, et al., Neurotrophic Factor-like Effect of FPF1070 on Septal Cholinergic Neurons After Transsections of Fimbria-fornix in the Rat Brain, Histol. Histopathol., 7 (1992), pp. 213221.

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29. E Masliah, F Armasolo, I Veinbergs, et al., Cerebrolysin Ameliorates Performance Deficits, and Neuronal Damage in Apolipoprotein E-deficient Mice, Pharmacol. Biochem. Behav., 62 (1999) 2, pp. 239245. 30. E Rockenstein, M Mallory, M Mante, et al., Effects of Cerebrolysin in Human APP Transgenic Animal Models of Alzheimers Disease, Neurobiol. Aging, 21 (2000), p. S168. 31. E Ruether, R Husmann, E Kinzler, et al., A 28 Week, Double-blind, Placebo-controlled Study with Cerebrolysin in Patients with Mild to Moderate Alzheimers Disease, Int. Clin. Psychopharm., 16 (2001), pp. 253263. 32. E Ruether , et al., Sustained Improvement of Cognition and Global Function in Patients with Moderately to Severe Alzheimers Disease: A Double-blind, Placebo-controlled Study with the Neurotrophic Agent Cerebrolysin, J. Neural Transm., 62 (2002) Suppl., pp. 265275.

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