cerebrolysin – a unique treatment option for alzheimer’s disease

B U S I N E S S B R I E F I N G : G L O B A L H E A L T H C A R E 2 0 0 3

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Technology & Services

a report by

EBEWE P h a rma

I n t r o d u c t i o n

Currently, there are an estimated 18 million peoplein the world with dementia. Of these, 12 million –two-thirds – live in developing countries. By 2025,the number of people with dementia will have nearlydoubled 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 developingand heavily populated regions such as China, Indiaand Latin America.

Alzheimer’s disease (AD) is a progressive neuro-degenerative disorder and is one of most prevalentdiseases of the elderly. In the classification of dementias,AD accounts for more than 60% of all dementias, whilevascular dementia is the second leading cause,accounting for an estimated 5% to 20% of cases.1 InJapan, vascular dementia is felt to be the most commoncause of dementia, accounting for ~50% of all dementiacases. Multiple different aetiologies of dementia mayco-exist. Indeed, macro- or micro-cerebrovasculardisease can further exacerbate an existing cognitiveimpairment due to AD.

An example of this is Germany. Assuming a meanprevalence of 6% to 8%, the number of dementedpersons in Germany lies between 770,000 and 1.2million. About 25% of these patients are aged between65 and 69 years, about 60% between 80 and 89 yearsand about 10% are over 90 years of age. Given theexpected increase in the number of elderly individualsamong the German population, which has beenestimated at an additional four million within the next50 years, one must anticipate that there will bebetween 1.1 and 1.6 million demented persons inGermany by 2050.2 The survival period with dementiaafter the onset of dementia symptoms decreases withthe patients’ age,3 with an average life expectancy of4.3 years in women and 3.3 years in men.4

Dementia is one of the most common causes forfunctional dependency and accounts for the largestproportion of disability in the elderly population.Several studies have shown that about 90% ofmoderately and severely demented individualsrequire permanent nursing home care5,6 and that

about 50% of all nursing home placements are dueto dementia.

C a r e o f D emen t e d P a t i e n t s

Several representative cross-sectional studies in thepopulation segment over 65 years of age in Germanyreported a total prevalence of 7% in need ofpermanent nursing care.7–9

The percentage of demented persons can actuallyonly be estimated, but existing studies indicate that50% to 70% of elderly persons who are in need ofcare 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 homeplacements are due to dementia.12–15

In industrialised countries, there is a trend towardsless family care and more institutionalised care due toseveral disease-imminent factors and demographicchanges. During the course of their illness, betweentwo-thirds and three-quarters of all dementedpatients are placed in nursing homes.9,16 Cross-sectional surveys show that at least 40% of alldemented patients are being cared for in nursinghomes, with a mean duration of institutionalisationranging from 2.6 to 3.1 years.16–19

The burden on the family members of the dementedpatients, usually spouses or daughters, is extremelyhigh. Future availability of such family care-giversupport is threatened by greater inter-generationalindependence as, in the future, an ever-increasingnumber of elderly people will be living alonewithout a younger relative nearby. Already morethan 40% of the elderly in Germany are currentlyliving alone. In the developed world, people withdementia live mainly on their own, or only withtheir spouse who also is elderly.

In developing countries, people with dementiamainly live in large extended family units, but this ischanging rapidly. Currently, 50% of all people withdementia live with at least four other persons. 25% ormore (50% in India) live in a three-generationhousehold with children under the age of 16. Persons

Cerebro ly s in – A Unique Treatment Opt ion for A l zhe imer ’s D i sease

with dementia still retain their senior status in thefamily. More than half in India and Nigeria are stillregarded as the head of the household.

With the mean duration of daily homecare rangingbetween six and 12 hours and approximately 50% ofthe care taking place at night, up to 40% of all care-givers fall ill themselves, frequently with depression,anxiety disorders or psychosomatic symptoms.20

Studies show that carers’ stress is mainly due tobehavioural disturbances of the patients, includingaggressive behaviour, and has no significantrelationship to cognitive impairment.17 Therefore,most nursing home placements are due to severebehavioural changes such as agitation and aggressionor severe impairments in physical function, such asincontinence. Both structured and informal socialsupport groups and intervention programmes tendto reduce the psychological stress of the care-giversand their morbidity; they also tend to delayinstitutional placement.20–22

T h e E c o n om i c Imp a c t o f D emen t i a

There are direct and indirect costs associated withdementia. Direct costs include diagnosis, in-patientand out-patient treatment, skilled nursing facility careand residential long-term care. Indirect costs mainlyinclude the losses of the family, such as loss ofproductive time of the care-giver, loss of lifetimeearnings owing to disability and premature mortality.The economic impacts can be judged in terms of lostincome and higher costs.

L o s t I n c o m e

In the developing world, dementia can be an evenmore difficult burden for the families of the patients,as some studies have demonstrated. A substantialproportion of care-givers have to reduce their paidwork or even to stop work altogether in order tocare for the person with dementia.

Care sometimes is also provided by other familymembers or by friends and neighbours in the localcommunity. Some of these care-givers also have tocut back on their paid work.

Fewer than 20% of people with dementia in Indiaand Nigeria, and around half in China and LatinAmerica, receive any retirement payments. Fewerthan 5% of the people with dementia receive anydisability benefits.

H i g h e r C o s t s

Families often employ additional professional care-givers, during the day and also at night. Theseprofessional care-givers must be paid.

People with dementia are heavy users of healthcare/social services. The costs amount to a substantialproportion of the average wage for a specificcountry. This is particularly the case for the poorerregions, e.g. India, China and Nigeria.

A cost analysis of dementia in Germany is still in anearly phase. Most research in terms of the economicimpact of dementia has been conducted in the USand the UK.14,15,23 One US investigation estimatedthe total cost for dementia at US$67.3 billion, withyearly total costs amounting to approximatelyUS$48.000 per patient.14 Assuming a prevalence of800,000 to 1.2 million demented persons inGermany, the total costs range between €35 and €56billion per year, with total costs per year perdemented patient totalling approximately €50,000.

All studies agree that the indirect costs of dementiaare 1.4 to 2.3-fold higher than the direct costs andaccount for up to 70% of total costs.23,24 Between50% to 70% of indirect costs are the result of familycare, while 55% to 75% of direct costs are due tolong-term residential care of demented patients.15

Costs increase with the severity of illness, due tomore frequent use of institutionalisation, short-termhospitalisation and the daily hours care-givers spendon caring.23

C e r e b r o l y s i n – A U n i q u e N e u r o t r o p h i cT r e a tmen t Op t i o n

At present, treatment of AD is largely restricted tosymptomatic interventions. The main therapeuticapproach to AD has been cholinergic transmitterreplacement, which led to the development ofcholinesterase inhibitors. Their overall efficacy,however, has been modest at best and they provideonly symptomatic benefit.25. Thus, stabilisingstrategies aiming at delaying disease progression arebeing investigated.26 Among others, treatment withneurotrophic agents is a promising alternative, withthe potential to modify the course of AD and delayits progression.

Among other lines of research, neurotrophic factortherapy has long been recognised as a promisingtreatment approach for AD.

Experimental studies have demonstrated that specificneurotrophic factors play a key role in maintainingcholinergic, noradrenergic and serotonergic neurons,cell populations that undergo progressivedegeneration in AD.27 Therefore, neurotrophicfactors or molecules that mimic the action of thesefactors potentially modify the course of AD and delayits progression.26

Cerebrolysin is a peptide preparation that has


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neurotrophic effects in various animal models ofAD.28,29 It is produced by a standardised enzymaticbreakdown of purified brain proteins and consists of25% low molecular weight peptides and free aminoacids. Cerebrolysin is currently approved andmarketed in 36 countries for the treatment of AD.

Clinical trials demonstrated the efficacy ofCerebrolysin in the treatment of AD afterintravenous (IV) application. The results of recentclinical trials suggest that Cerebrolysin has – beyondits symptomatic effect – a unique stabilising effect inpatients with AD.

Cerebrolysin displays neurotrophic and neuro-protective activity in vitro and in vivo. In contrast tonerve growth factors, Cerebrolysin causes this effectafter peripheral injection, suggesting that the smallmolecules are able to penetrate the blood-brainbarrier in pharmacodynamically significant amounts.

In a model of fimbria-fornix transsection, Cerebrolysinprevented degeneration of medial septal cholinergicneurons and improved lesion-induced cognitivedeficits in animals.28 Significant improvements inlearning and memory were also achieved in oldanimals, which were associated with a significantincrease in synaptic density in the hippocampus and theentorhinal cortex. In a model of apolipoprotein-Eknock-out mice, Cerebrolysin improved the cognitivedeficits and exhibited morphological effects, suggestinga normalisation of the impaired neuronal cytoarchi-tecture.29 In transgenic mice over-expressing amyloidprecursor protein, Cerebrolysin reduced Aß1–42 loadand counteracted behavioural deficits. Cerebrolysinimproved spatial orientation learning and memory, andhistological examinations of the brains of the animalsrevealed a significant increase in synaptic density.30

To date, the clinical database for Cerebrolysinencompasses more than 80 clinical trials with over5,000 patients; the majority of the patients in theseclinical trials had dementia, in particular AD.Patients were enrolled into these clinical trials if theywere suffering from mild to moderate AD accordingto the National Institute of Neurological andCommunicative Disorders and Stroke and theAlzheimer’s Disease and Related DisordersAssociation (NINCDS-ADRDA) or InternationalClassification of Disorders (ICD) criteria, and hadMini Mental State Examination (MMSE) scores of12 to 26. All patients were treated with IV infusionsof 30ml Cerebrolysin (or placebo) five days perweek for four weeks, with the exception of twostudies in which this regimen was repeated after atreatment-free interval of two months. The clinicalfollow-up ranged from one month in the earlierstudies up to seven months in the more recentlycompleted trials.

In these clinical trials, the beneficial effects ofCerebrolysin on various domains of AD, includingcognitive performance, global function and activitiesof daily living, have been demonstrated. In thefollowing, the results of recently completed,randomised, placebo-controlled, double-blindclinical trial are summarised and reviewed.

The vast majority of the clinical trials withCerebrolysin in AD to date focused on mild tomoderate AD patients with MMSE scores rangingfrom 12 to 26. One example is the clinical trial by ERuether and colleagues.31

To evaluate the efficacy of Cerebrolysin in patientswith more advanced AD, a subset analysis of patientsenrolled in the above-mentioned recently completedclinical trial was performed. This subgroup analysisincluded patients with moderate to moderatelysevere 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 with149 patients. The clinical trial was conducted inGermany and Austria according to InternationalConference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticalsfor Human Use International Conference onHarmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human UseGood Clinical Practice (ICH-GCP) guidelines.Written informed consent was provided by thepatient and the care-giver. The full details arepublished as mentioned above. Of the full patientsample, 109 had aN MMSE score of less than 20, andthese patients were included in the subset analysis(Cerebrolysin n=60; placebo n=49).

E f f i c a c y

A responder analysis showed that 65% ofCerebrolysin-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. Duringthis follow-up examination, 48.3% of theCerebrolysin patients had improvement of globalfunction from baseline, in contrast to only 16.3% ofthe placebo patients (p=0.005). This indicates thatthe beneficial effects of Cerebrolysin weremaintained for three months after drug withdrawal.

Comparable results were observed in the cognitivedomain. On the Alzheimer's Disease AssessmentScale - cognitive subscale (ADAS-cog), a significanteffect of Cerebrolysin was observed at week 16, withresponder rates of 55% for Cerebrolysin, compared


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with 16.3% for placebo (p=0.001). Patients onCerebrolysin had an improvement from a baseline of-3.0 points, while placebo patients worsened by 1.1points, accounting for a treatment difference of -4.1points in favour of Cerebrolysin (p<0.001). Thebeneficial effect of Cerebrolysin was maintained untilweek 28, with a group difference of -2.8 points infavour of Cerebrolysin (p=0.004).

Improvement of cognitive function correlated wellwith 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 (4points in the ADAS-cog. This fraction was muchlower in the placebo group, with only 10% of thepatients meeting both the CGI and ADAS-cogresponse criteria (p=0.002).

The group difference in the CGI score is 0.75 pointsin favour of Cerebrolysin and is among the highestreported in the medical literature.

The results of the secondary outcome measuresprovided supportive evidence for the efficacy ofCerebrolysin. In the activities of daily living(Nuremberg Activities Inventory (NAI) score),despite not reaching statistical significance, there wasa clear trend (p=0.1) in favour of Cerebrolysin witha drug-placebo difference of 0.6 points at week 16.

Significant superiority of Cerebrolysin over placebowas evident in the behavioural domain. The treatmentdifference in the ADAS-noncog at week 16 was -1.3points in favour of Cerebrolysin (p=0.002). Thisfavourable effect was not only maintained, but itincreased after the washout phase. At week 28, patientson Cerebrolysin had improved by -0.2 point, whereas

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

S a f e t y

The overall incidence of the adverse effects (AEs)was similar in both treatment groups: 43.4% of theCerebrolysin patients, compared with 38.0% of theplacebo patients, experienced at least one AE. MostAEs were rated mild in both treatment groups. Themost common AEs reported by patients onCerebrolysin were vertigo, headache, sweating andnausea. These AEs, however, occurred with a similarfrequency in the placebo group. Cerebrolysin waswell tolerated.

This clinical trial demonstrates that IV treatment withCerebrolysin results in statistically and clinicallysignificant improvement of global function, cognitiveperformance and behavioural performance in patientswith moderate to moderately severe AD. The resultsare in accordance with the data of the full sample,where Cererbolysin was significantly superior toplacebo. This subset analysis demonstrated an evenslightly higher positive treatment effect in patientswith more advanced disease.

This data points to a possible disease modifyingaction and a stabilising effect of Cerebrolysin in AD,which goes far beyond a pure symptomatic effect.This is in agreement with the reported neurotrophicactivity of Cerebrolysin.

In conclusion, the neurotrophic compoundCerebrolysin leads to statistically significant andclinically relevant improvements of cognitiveperformance and global function in patients withmoderate to moderately severe AD. The therapeuticbenefit is maintained in part for at least three monthsafter drug withdrawal, suggesting a stabilising effect ofCerebrolysin in patients with AD. Cerebrolysin fulfilsthe requirements of a modern therapy for AD; itimproves 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 wellas the burden on the healthcare budget. ■



Contact Information

EBEWE Pharma

Mondseestraße 11

A-4866 Unterach

Austria

Tel: (43) 7665 8123 0

Fax: (43) 7665 8123 11

http://www.ebewe.com

e-Mail: [email protected]

Figure 1: Time Course of the ADAS-noncog

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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29. E Masliah, F Armasolo, I Veinbergs, et al., “Cerebrolysin Ameliorates Performance Deficits, and Neuronal Damage inApolipoprotein E-deficient Mice”, Pharmacol. Biochem. Behav., 62 (1999) 2, pp. 239–245.

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32. E Ruether , et al., “Sustained Improvement of Cognition and Global Function in Patients with Moderately to SevereAlzheimer’s Disease: A Double-blind, Placebo-controlled Study with the Neurotrophic Agent Cerebrolysin”, J. NeuralTransm., 62 (2002) Suppl., pp. 265–275.


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cerebrolysin – a unique treatment option for alzheimer’s disease

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