Evidence-based review of current Parkinson’s disease treatments

This educational material has been supported by Abbott

Evidence-based review of current Parkinson’s disease treatments

Subcutaneous apomorphine infusion treatment<<Insert speaker’s name and affiliation here>>

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

• 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

• 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

• 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

• 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

Study Difference 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 - 85 NR - 45 7 11

2 - 67 NR - 20 9 10

3 - 77 NR NR 14 26

4 - 57 NR - 40 10 12

5 - 59 NR NR 22 36

6 - 58 NR NR 7 3

7 - 50 -12 - 14 25 44

8 - 42 NR NR 34 30

9 - 40 NR NR 11 12

10 - 80 -61 NR 12 24

11 - 60 NR - 48 12 24

12 - 38 NR - 58 12 6

13 - 51 NR + 3 13 12

Apomorphine in Parkinson’s disease, 2nd 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

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

Study Number Follow-up Monotherapy ‘On’-duration

‘Off’-duration

Dyskinesias

Colzi et al, 1998

19 12 m 19 71% ↓65% severity

↓85% duration

Manson et al, 2002

63 36 m 45/63 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

↑

↑

• 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

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)

UP

DR

S-3

ON

(O

FF

) sc

ore*

*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.

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

Effect of apomorphine on non-motor symptoms in advanced Parkinson’s disease

Naidu Y,et al. Mov Disord 2009;24(Suppl1):S360.

Effect of apomorphine on non-motor symptoms and quality of life

Naidu Y,et al. Mov Disord 2009;24(Suppl1):S360.

Side effects* Intermittent injection (N=165)

Continuous infusion (N=212)

Local cutaneous/SC reactions• Nodules, itching, bruises, etc. 69 159

Neuropsychiatric• Non-defined• Sedation• Hallucination

7217

93923

Systemic/other• Nausea• Orthostatic hypotension• Eosinophilia• Rhinorrhoea• Vertigo/dizziness• Yawning

2562669

12159230

‘Apomorphine in Parkinson’s disease’, 2nd 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

Study Design / follow-up Results

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

Study Design/ follow-up Results

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, 2004 • 123 patients • 17 patients (9 apomorphine) with punding associated with high doses of dopamine replacement therapy

Tellez et al, 2006 • Case 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

• 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