1. Evidence-based review of current Parkinson’s disease treatments This educational material has been supported by Abbott

2. Evidence-based review of current Parkinson’s disease treatments Subcutaneous apomorphine infusion treatment >

3. Learning objectives At the end of this section you will: Be aware of the current evidence base for subcutaneous apomorphine infusion in the treatment of advanced Parkinson’s disease Know the clinical findings for subcutaneous apomorphine infusion in the alleviation of motor complications Gain greater knowledge of the tolerability profile of subcutaneous apomorphine infusion

4. Most potent dopamine agonist Low bioavailability  parenteral use Clinical effect: Extent: identical to levodopa Onset: faster (5-20, max 60 min) Duration: shorter (  40 min) Randomised controlled study: ‘Off’  34% = 2 hours (p=0.02) Dyskinesias: Apo  35%, placebo 11% Review: ‘Off ’  46%, ‘ON’ with dyskinesias: +33% Dewey RB, et al. Arch Neurol 2001;58:1385-92. Deleu D, et al. Drugs Aging 2004;21:687-709. Apomorphine

5. Apomorphine is administered subcutaneously into the fatty tissue of the abdominal area, or alternatively into the upper thighs and arms Almost 100% of the drug is absorbed into the blood stream The apomorphine pump is about the size of a mobile phone and may be worn on a waistband of trousers or a skirt or alternatively hidden under clothes Frankel JP, et al. J Neurol Neurosurg Psychiatry 1990;53:96-101. European Parkinson’s Disease Association. Available at; http://epda.eu.com/medinfo/apomorphine (accessed 24 June 2010) Subcutaneous apomorphine infusion

6. Patient selection and information Reimbursement issues Baseline assessments including blood tests, Coombs test Premedication: domperidone 60 mg/d for ≥ 3 days Hospital admission Initial flow rate 1 mg/h which is gradually increased, depending on tolerability and efficacy Target dose: –Mean doses: studies where monotherapy was aimed at 100 mg/d –Add-on to oral treatment approximately 70 mg/d Concomitant reduction of oral medication, starting with dopamine agonists, monamine oxidase inhibitors, amantadine, then levodopa Subcutaneous apomorphine infusion: Practical issues

7. Instruction and training in pump handling and later supervision is given to patients and carers Infusion is given ideally by the patients themselves or if necessary carers European Parkinson’s Disease Association. Available at: http.//epda.eu.com/medinfo/apomorphine (accessed 24 June 2010). Subcutaneous apomorphine infusion: Practical approach

8. StudyDifference in recordings within a motor state (%) before and after subcutaneous apomorphine infusion treatment Patients (N)Time (months) Time in ‘off’ (%)Time in ‘on’ with dyskinesias (%) Dyskinesia intensity 1- 85NR- 45 7 11 2 - 67NR- 20910 3 - 77NR 1426 4 - 57NR- 401012 5 - 59NR 2236 6 - 58NR 73 7 - 50-12- 142544 8 - 42NR 3430 9 - 40NR 1112 10 - 80-61NR1224 11 - 60NR- 481224 12 - 38NR- 58126 13 - 51NR+ 31312 Apomorphine in Parkinson’s disease, 2 nd edition. Ed. Odin P, Hagell P, and Shing M. 2008. Uni-Med Verlag. Reproduced with kind permission of Per Odin Subcutaneous apomorphine infusion: Overview of clinical efficacy NR=not reported

9. Early literature: Mean ‘off’ duration 65%  Reduction in dyskinesias observed in some studies: Levodopa 1260  280 mg/d Frankel JP, et al. J Neurol Neurosurg Psychiatry 1990;53:96-101. Hughes AJ, et al. Mov Disord 1993;8:165-70. Pietz K, et al. J Neurol Neurosurg Psychiatry 1998;65:709-16. Poewe W, et al. Adv Neurol 1993;60:656-9. Wenning GK, et al. Adv Neurol 1999;80:545-8. Subcutaneous apomorphine infusion

10. StudyNumberFollow-upMonotherapy‘On’-duration‘Off’- duration Dyskinesias Colzi et al, 1998 1912 m1971%↓65% severity ↓85% duration Manson et al, 2002 6336 m45/63 52% monotherapy ↓63% monotherapy 32% polytherapy ↓32% polytherapy Time to significant reduction 4.6 m Monotherapy = apomorphine only during waking day except morning / night time Colzi A, et al. J Neurol Neurosurg Psychiatry 1998;64:573-76. Manson AJ, et al. Mov Disord 2002;17:1235-41. Subcutaneous apomorphine infusion ↑ ↑

11. Levodopa/apomorphine single dose challenges before/after 6 months’ treatment, blinded raters AIMS and Rush scores ↓ 36-44%; correlation of improvement with oral dose reduction Daily ‘off’ time: ↓ 38% (=2.4 hours) Katzenschlager R, et al. Mov Disord 2005;20:151-7. Subcutaneous apomorphine infusion: Short-term prospective analysis

12. Subcutaneous apomorphine infusion: Long-term prospective analysis Apomorphine (N=12) versus DBS (N=13) Up to 5 years’ follow-up Average duration on apomorphine = 30 months Comparable levodopa equivalent dose reduction between treatments Daily ‘off’’ time: –↓ 49% (Apo) –↓ 91% (DBS) DBS only: - 80% and - 83% dyskinesia duration and severity, respectively DBS only: significantly worsened neuropsychological function (NPI, verbal fluency; p<0.05 versus baseline) UPDRS-3 ON (OFF) score* *Intention-to-treat analysis; apomorphine: two of 12 subjects reached 5-year follow-up; DBS: 12 of 13 subjects were followed up at 5 years; DBS = deep brain stimulation; NPI = neuropsychiatric inventory Antonini A, et al. J Neurol 2011;258:579-585.

13. Long-term subcutaneous apomorphine infusion therapy Long-term retrospective observational study, 35 centres 4 years: 82/166 patients remained on pump. Levodopa dose (mg/d): 1405 → 800 (p<0.0001) ‘Off’: 6.64 → 1.36 hours/d (p<0.0001) (- 80%) Dyskinesia severity: - 31% Open, uncontrolled Dyskinesia reduction maintained over 5 years Compared to medical treatment (patients’ choice): Mean APO dose: 100 mg/d ‘Off’ reduction: 40% Dyskinesia reduction (AIMS): - 37% Stocchi F, et al. Neurol Sci 2001;22:93-4. Di Rosa AE, et al. Neurol Sci 2003;24:174-5.Garcia-Ruiz PJ, et al. Mov Disord 2008;23:1130-6. Copyright 2001. Reprinted with permission of Springer Verlag, Inc

14. Effect of apomorphine on non-motor symptoms in advanced Parkinson’s disease Naidu Y,et al. Mov Disord 2009;24(Suppl1):S360.

15. Effect of apomorphine on non-motor symptoms and quality of life Naidu Y,et al. Mov Disord 2009;24(Suppl1):S360.

16. Side effects*Intermittent injection (N=165) Continuous infusion (N=212) Local cutaneous/SC reactions Nodules, itching, bruises, etc.69159 Neuropsychiatric Non-defined Sedation Hallucination 7 21 7 9 39 23 Systemic/other Nausea Orthostatic hypotension Eosinophilia Rhinorrhoea Vertigo/dizziness Yawning 25 6 2 6 9 12 15 9 2 3 0 ‘Apomorphine in Parkinson’s disease’, 2 nd edition. Ed. Odin P, Hagell P, and Shing M. 2008. Uni-Med Verlag, Manson AJ, et al Mov Disord 2002;17:1236-41. *In addition: - Haemolytic anaemia: frequency unknown, positive Coombs test in ≤ 12.5%: Regular blood tests required (Manson et al. 2002) - Dopaminergic dysregulation syndrome and punding Apomorphine adverse events

17. StudyDesign / follow-upResults Alegret et al, 2004* (1 year) DBS, N=9 Apomorphine, N=7 DBS waiting list Apomorphine: no change DBS: at 6 months, significantly worse on word fluency and Stroop naming; at 1 year, partially reversible De Gaspari et al, 2006* (1 year) DBS, N=13; Apomorphine, N=12 Patients’ choice ‘Off’  : both; dyskinesias: only DBS significantly , but: levodopa  only by 29% MMSE: unchanged Only DBS: significantly worse apathy, anxiety, depression, hypomania (NPI), verbal fluency Di Rosa et al, 2003* (1 year) Levodopa (oral), Apomorphine, N=12 Apomorphine: 100 mg/d; levodopa: 55%  ; ‘off’, AIMS significantly improved 1 year: significant improvement in Beck Depression scale on APO only Morgante et al, 2004* (2 years) Rater-blinded, patients’ choice Cognition (MMSE; Brief Psychiatric Rating Scale): same *Comparative but not randomized studies; patients on DBS waiting list or patients’ choice DBS = deep brain stimulation; MMSE = Mini Mental State Examination Alegret M, et al. Mov Disord 2004;19:1463-9. De Gaspari D, et al. J Neurol Neurosurg Psychiatry 2006;77:450-3. Di Rosa AE, et al. Neurol Sci 2003;24:174-5. Morgante L, et al. Arch Gerontol Geriatr Suppl 2004;9:291-6. Subcutaneous apomorphine infusion: Neuropsychiatric adverse events

18. StudyDesign/ follow-upResults Van Laar et al, 2010 Uncontrolled study, 10 patients with visual hallucinations Apomorphine pump 6 weeks Significant improvement in hallucinations (Neuropsychiatric Inventory) and caregiver distress Evans et al, 2004123 patients17 patients (9 apomorphine) with punding associated with high doses of dopamine replacement therapy Tellez et al, 2006Case study, 1 patient Single case of patient with presumed dopamine dysregulation syndrome (‘addiction’) van Laar T, et al. Parkinsonism Relat Disord 2010;16:71-27. Tellez C, et al. Addiction 2006;101:1662-1665. Evans AH, et al. Mov Disord. 2004;19:397-405. Subcutaneous apomorphine infusion: Neuropsychiatric adverse events, continued

19. Subcutaneous apomorphine infusion is effective for treatment of the symptoms of Parkinson’s disease Subcutaneous apomorphine infusion has fewer contraindications than deep brain stimulation (DBS) Observations of reversible motor complication phenomena with subcutaneous apomorphine infusion are consistent with concept of continuous dopaminergic stimulation Randomised controlled studies of subcutaneous apomorphine infusion compared to oral treatment, intrajejunal levodopa and DBS are warranted Summary