Cerebrolysin – Treatment without limitations Clinical bene­fits for patients and caregivers Diagnostic problems • Decelerate cognitive decline • Improvement of memory and concentration 1 RUETHER, E., et al. A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer’s disease. International clinical psychopharmacology, 2001, 16. Jg., Nr. 5, S. 253-263 • Stay active in social life 2 GUEKHT, Alla B., et al. Cerebrolysin in vascular : improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter TBI • Live a fully independent life trial. Journal of Stroke and Cerebrovascular Diseases, 2011, 20. Jg., nr. 4, S. 310-318 3 ALVAREZ, X. A., et al. A 24‐week, double‐blind, placebo‐controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer’s disea- • Reduced support from caregivers needed se. European journal of neurology, 2006, 13. Jg., Nr. 1, S. 43-54 • Prevent behavior symptoms and the destruction of 4 GAUTHIER, Serge, et al. Cerebrolysin in mild-to-moderate Alzheimer’s disease: a meta-analysis of randomized controlled clinical trials. Dementia and geriatric cognitive disorders, 2015, 39. Jg., Nr. 5-6, S. 332-347 personality Lack of Lack of Lack of 5 Chen, N., Yang, M., Guo, J., Zhou, M., Zhu, C., & He, L. (2013). Cerebrolysin for . Cochrane Database Syst. Rev, 1. NEUROCOGNITIVE • Increase quality of life DISORDERS time test instruments solid criteria/biomarkers

No matter of No matter of type No matter of course Administration stage of the disease of neurocognitive disorder of the disease CEREBROLYSIN FITS TO ALL Disorder Daily dosage Initiation of treatment Treatment Duration Route of administration

2 – 4 cycles / year Vascular dementia 10 – 30 ml as soon as possible • IV injection for 3 min: Up 1 cycle = 5 days weekly / 4 weeks to 10 ml undiltuted • IV injection for Mild Moderate Mild Moderate Severe 2 – 4 cycles / year Alzheimer‘s disease 10 – 30 ml as soon as possible 15 – 60 min: 10 ml - 50 ml Effective treatment for MCI MCI Dementia Dementia Dementia 1 cycle = 5 days weekly / 4 weeks diltuted to at least 100 ml total volume with saline, Ringer solution Neurocognitive Disorders others Stroke 20 – 50 ml as soon as possible 10 – 21 days for 5% glucose solution vascular mixed dementia dementia • 5 ml dosage (undiltuted) with Cerebrolysin® Traumatic brain can by administered 20 – 50 ml as soon as possible 7– 30 days Tauopathies injury intramusculary

Alzheimer disease

Cerebrolysin® is a multi-modal neuropeptide ONE FOR ALL drug that helps to maintain the independence Copyright © 2018 by EVER Neuro Pharma GmbH, Oberburgau 3, 4866 Unterach, Austria. All rights reserved. No part of this brochure may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher. Cerebrolysin of patients suffering from neurocognitive is a registered trademark of EVER Neuro Pharma GmbH, 4866 Unterach, Austria. ABBREVIATED PRESCRIBING INFORMATION - Cerebrolysin disorders Name of the medicinal product: Cerebrolysin® - Solution for injection. Qualitative and quantitative composition: One ml contains 215.2 mg of porcine brain-derived preparation (Cerebrolysin® concentrate) in aqueous solution. List of excipients: Sodium hydroxide and water for injection. Therapeutic indications: Organic, metabolic and neurodegenerative disorders of the brain, especially senile dementia of Alzheimer‘s type - Post-apoplectic complications - Craniocerebral trauma; CEREBROLYSIN FITS TO ALL post-operative trauma, cerebral contusion or concussion. Contraindications: Hypersensitivity to one of the components of the drug, epilepsy, severe renal impair- ment. Marketing Authorisation Holder: EVER Neuro Pharma GmbH, A-4866 Unterach. Only available on prescription and in pharmacies. More information about pharmaceutical form, posology and method of administration, special warnings and precautions for use, interaction with other medicinal products and other forms of interaction, fertility, pregnancy and lactation, effects on ability to drive and use machines, undesirable effects, overdose, pharmacodynamics properties, pharma- Cognitive Activities Global Behavior & psychiatric cokinetic properties, preclinical safety data, incompatibilities, shelf life, special precautions for storage, nature and contents of the container and special precautions impairment of daily living function symptoms for disposal is available in the summary of product characteristics. (Reference SPC – CCDS Version 1.0/Jan 28 2014)

EVER Neuro Pharma GmbH Oberburgau 3 4866 Unterach Austria www.everpharma.com www.cerebrolysin.com

Reconnecting Neurons. CERE/INT/06/2018/11 Empowering for Life. Cognitive Cerebrolysin significantly Activities of Prolong active and independent Global Better quality of life for patients Behavior & psychiatric Cerebrolysin improves behavior & impairment improves cognitive performance! daily living life with Cerebrolysin! functions and caregivers with Cerebrolysin! symptoms neuropsychiatric symptoms!

Early and long-term beneficial effects on cognitive performance Cerebrolysin increases level of activities of daily living Phenomenal NNT of 2.9 with Cerebrolysin Improvement of behavior problems which facilitate home care

• Treat 3 patients and one ADCS-ADL Cerebrolysin Placebo ADAS-noncog Cerebrolysin Placebo BENEFIT (number needed to treat for bene t): 2.9 RISK (number needed to treat for harm): 501 ADAS-cog 30 ml Cerebrolysin/MMSE ≤ 20 additional patient shows 30 ml Cerebrolysin/MMSE 14 – 24 • Significant improvements 60 significant beneficial effects -2 • Significant cognitive improvements with 59 p<0.01 p<0.01 of behavior in Cerebrolysin 58 • Significant superiority of • Positive benefit-risk relation Cerebrolysin -1 group 57 p<0.05 5 Cerebrolysin in ADCS-ADL score in favour of Cerebrolysin

p<0.001 56 improvement • After 7 months Cerebrolysin • Immediate treatment effects during each 0 55 • NNT for benefit shows a 4 treatment cycle • Constant improvements in p<0.01 treated patients still p<0.001 p<0.014 54 significant global clinical

Cerebrolysin group while patients decline 3 53 1 improved in the p<0.025 • Cerebrolysin shows highest effect after second change of 2.9 52 in placebo group are unchanged Mean change from baseline ADAS-noncog, while

ADAS-cog 2 treatment cycle

Mean scores (LS means) 51 2 4 • Lowest NNT for harm with patients in the placebo 50 • Even within the follow-up-period Figure 5 – NNT for benefit and for harm of Cerebrolysin, Gauthier et al. 2015 (AD) 1 • Efficacy difference of 3.2 points in favour of Treatment Follow-up Treatment Follow-up group have worsened 49 consistent enhancements in respect to risk (501) 3 Treatment Follow-up Treatment Follow-up Baseline 1 3 4 6 (treatment di erence to placebo) 0 Cerebrolysin on month 7 confirms long-term Cerebrolysin group 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 effects Time (months) Time (months) Time (months) Figure 7 – Improvement/Decline of ADAS-noncog in patients treated Cerebrolysin Figure 3 – ADCS-ADL mean value in patients treated Cerebrolysin or placebo, 1 2 or placebo, Ruether et al. 2001 (AD) Figure 1 – Long term positive outcome indicating disease modifying Guekht et al. 2011 (VD) 100% higher quality of life with Cerebrolysin and stabilizing effects of the treatment, Ruether et al. 2001 (AD)1

Significant improvement of neuropsychiatric symptoms CIBIC+ Values are % = % of patients Decelerate cognitive decline with Cerebrolysin Regain independence with Cerebrolysin • CIBIC+ assessment showed Cerebrolysin Placebo a significant shift toward 17.0% 17.4% • Improvements in the NPI improvement in the Improvement Improvement 7.7% score in all Cerebrolysin NPI Cerebrolysin group when No change 45.2% No change groups Cerebrolysin 10ml Cerebrolysin 30ml Cerebrolysin 60ml Placebo Deterioration Deterioration DAD Cerebrolysin 10ml Cerebrolysin 30ml Placebo compared to placebo 75.3% 37.4% ADAS-cog + Cerebrolysin Placebo -6 • At month 6 all groups treated p<0.05 • Significant superiority of • Best results with a daily • In Cerebrolysin group -5 * p<0.001 Negative values depict improvement 5 with Cerebrolysin significantly -12 -4 Cerebrolysin dosage of 30 ml 4 majority of patients showed improved and maintained (LS means) * p<0.05 p<0.1 improvement (75.3% vs. 37.4% -3 -10 * 3 p<0.1 the beneficial effects of • ADAS-cog+ least squares • Dose of 30 ml Cerebrolysin CIBIC+ Cerebrolysin Placebo p<0.0001 Values are % = % of patients -2 2 in placebo group) (LS means) neuropsychiatric symptoms -1 (LS) mean change from -8 * exerts a beneficial effect on 6.2 1 45.2 0 5.3 p=0.064 p=0.069 p=0.183 improvement baseline was –10.6 points in patients capabilities to cope 0 • In placebo group majority of -6 • Placebo patients deteriorated 1 the Cerebrolysin group vs. * 3.9 with ADL -1 patients remained unchanged 36.8 32.5 from their baseline 2 LS Mean –4.4 points in the placebo -4 -2 decline 2.7 • Even in the follow-up time • Lines show exact this picture – Change from baseline 3 group -3 23.5 • At all time points the Active treatment Follow-up -2 4 Cerebrolysin treated patients -4 Highest point of curve in 17.1 0 1 2 3 4 5 6 12.2 13.9 dosage of 60 ml is the most Change from baseline Treatment 2 Treatment 1 Treatment Follow-up Treatment Follow-up Follow-up Responders (%) • 6.2 points treatment difference show better results than in the -5 the area of improvement 7.7 Time (months) 0 6.0 3.5 effective one – even further 0 1 2 3 4 5 6 1.7 in favour of Cerebrolysin 0 1 2 3 4 5 6 beginning in Cerebrolysin group vs. in 0 0.0 0.0 Time (months) improvements in the follow- Figure 8 – Neuropsychiatric Inventory (NPI) change from baseline in patients treated Marked Moderate Minimal No change Minimal Moderate Marked Time (months) the area of no change in the 3 improvement improvement improvement worsening worsening worsening up period was shown in this with different doses of Cerebrolysin or placebo, Alvarez et al. 2006 (AD) Figure 2 – ADAS-cog+ change from baseline in patients treated Cerebrolysin or placebo, Figure 4 – Improvement/Decline of DAD in patients treated with different doses placebo group 2 group Guekht et al. 2011 (VD) of Cerebrolysin or placebo, Alvarez et al. 2006 (AD)3 Figure 6 – Impact of Cerebrolysin on global functions (CIBIC+) in VaD patients treated with Cerebrolysin or placebo, Guekht et al. 2011 (VD)2

Alvarez triggered inclusion in the Austrian Alzheimer’s disease guideline3 Cochrane review “Use of Cerebrolysin in the treatment of vascular dementia” confirms the efficacy of Cerebrolysin in the therapy of cognitive impairment5