1. When the going gets tough…. How to select patients with Parkinson’s disease for advanced therapies Dr Paul Worth PhD FRCP Consultant Neurologist, Addenbrooke’s Hospital, Cambridge and West Suffolk Hospital, Bury St Edmunds Date of preparation: August 2014 Prescribing information and SPC can be found on the landing page of the extranet site AXDUO131759a(1) Slide 1 of 31

2. Prescribing information and SPC can be found on the landing page of the extranet site

3. The Clinical Problem A 67 year old man with a 10 year history of PD presents with increasing walking difficulties and has developed worsening fluctuations in the control of his motor symptoms. He was originally treated with ropinirole and levodopa was added after 3 years as his symptoms worsened. He began to notice ‘wearing off’ 4 years ago and despite levodopa fractionation, addition of entacapone and rasagiline, he is spending 5 hours a day ‘OFF’, and has developed moderately severe peak dose dyskinesias. Tolcapone resulted in severe diarrhoea. Prescribing information and SPC can be found on the landing page of the extranet site

4. On Dopaminergic treatment Disease Progression Off Dyskinesia Prescribing information and SPC can be found on the landing page of the extranet site

5. On Dopaminergic treatment Disease Progression Off Dyskinesia Prescribing information and SPC can be found on the landing page of the extranet site

6. On Dopaminergic treatment Disease Progression Off Dyskinesia Prescribing information and SPC can be found on the landing page of the extranet site

7. On Dopaminergic treatment Disease Progression Off Dyskinesia Prescribing information and SPC can be found on the landing page of the extranet site

8. n Off On Dyskinesia On Dyskinesia Off On Dyskinesia Prescribing information and SPC can be found on the landing page of the extranet site

9. TDS dosing Prescribing information and SPC can be found on the landing page of the extranet site

10. Fractionated dosing Prescribing information and SPC can be found on the landing page of the extranet site

11. # Patch or extended-release dopamine agonist Prescribing information and SPC can be found on the landing page of the extranet site

12. Overview Importance of early identification of patients failing on conventional medications When do we have conversations with patients? Which patients are likely to benefit? What benefits can be expected? How do we select one device-aided therapy over another? Prescribing information and SPC can be found on the landing page of the extranet site

13. Facts All patients that are suitable for advanced therapies now have access to them Not all patients with access to advanced therapies are referred in a timely fashion Result: some patients who would benefit are referred too late and some never at all Prescribing information and SPC can be found on the landing page of the extranet site

14. Lack of information and access to advanced treatment for PD patients - Survey Swedish survey of >3000 PD patients, ~ ⅓ had advanced PD Three quarters had heard of advanced therapies but said they were ‘denied’ treatment < 30% of respondents with advanced disease had heard about one or other of the therapies from their doctor directly Lökk J. J Multidiscip Healthc. 2011; 4: 433-439. Prescribing information and SPC can be found on the landing page of the extranet site

15. The ‘Right’ Therapy at the ‘Right’ Time How do I recognise the patient who will not benefit from further adjustments to conventional therapy? How do I decide which therapy is most likely to benefit a particular patient? Prescribing information and SPC can be found on the landing page of the extranet site

16. Discussion At what point in the patient’s journey do we have conversations about future advanced therapies? Prescribing information and SPC can be found on the landing page of the extranet site

17. Tips for identifying (not missing!) suitable patients Care plan Persistent failure to be able to perform ADLs consistently in spite of ‘optimised’ therapy Young onset patients particularly at risk – Wearing off questionnaire Avoid strict limits as to daily OFF time needed for referral Worth PF. Pract Neurol. 2013; 0: 1-13. doi: 10.1136/practneurol-2012-000463. Prescribing information and SPC can be found on the landing page of the extranet site

18. Prerequisites for consideration of advanced therapies Idiopathic Parkinson’s disease Clear levodopa-responsiveness Exclude frank dementia, chronic hallucinosis / psychosis Unrealistic expectations – Levodopa-unresponsive axial symptoms – NMS – Not a cure Worth PF. Pract Neurol. 2013; 0: 1-13. doi: 10.1136/practneurol-2012-000463. Prescribing information and SPC can be found on the landing page of the extranet site

19. Levodopa-unresponsive axial symptoms Freezing of gait (FOG) in the ON state Dysarthria Dysphagia Falls because of loss of postural reflexes Worth PF. Pract Neurol. 2013; 0: 1-13. doi: 10.1136/practneurol-2012-000463. Prescribing information and SPC can be found on the landing page of the extranet site

20. Advanced therapies Prescribing information and SPC can be found on the landing page of the extranet site

21. Common Themes Infusion therapies get round problem of delayed gastric emptying Allow reduction in other PD medications 24 hour therapy unlicensed but possible Continuous (dopaminergic) stimulation Prescribing information and SPC can be found on the landing page of the extranet site

22. ‘Known knowns’ or ‘unknown unknowns’? With respect to these three therapies, what are the comparative: – Efficacies? – Adverse event profiles? – QoL data? – Cost effectiveness data? – Long term efficacies? Prescribing information and SPC can be found on the landing page of the extranet site

23. Review Conclusions Systemic review of apomorphine infusion, levodopa infusion and deep brain stimulation in advanced Parkinson's disease No randomised trials comparing three treatment modalities Selection of a given therapy depends on patient and clinician preference Clarke CE, Worth P, Groset D, Stewart D. Parkinsonism and Related Disorders. 2009; 15: 728-741. Prescribing information and SPC can be found on the landing page of the extranet site

24. What benefits can patients expect from each therapy? All 3 therapies aim to provide a: Reduction in OFF time and increase in ON time Reduction in dyskinesia Improved quality of life Worth PF. Pract Neurol. 2013; 0: 1-13. doi: 10.1136/practneurol-2012-000463. Prescribing information and SPC can be found on the landing page of the extranet site

25. Apomorphine adverse events include Neuropsychiatric disturbances (including transient mild confusion and visual hallucinations) Transient sedation Somnolence Subcutaneous nodules Yawning Nausea/vomiting Dizziness and light headedness APO-go Ampoules 10mg/ml Solution SmPC available from http://www.medicines.org.uk/emc Last accessed February 2014 Prescribing information and SPC can be found on the landing page of the extranet site Note: These are common (≥1/100 to <1/10) adverse events

26. DBS adverse events Surgery-related Intracranial haemorrhage (3.9%) Device malfunction, infection (1.7%), or migration of leads Cumulative rate approx 11% Stimulation-related Dysarthria (9.3%) Weight gain (8.4%) Depression (6.8%) Eyelid opening apraxia (3.6%) Dyskinesias (2.6%) Manic episodes (1.9%) Kleiner-Fisman G, et al. Movement Disorders. 2006; 21(suppl. 14): s290-s304. Prescribing information and SPC can be found on the landing page of the extranet site

27. LCIG adverse events Devos D. Movement Disorders. 2006; 24(7): 993-1000. Prescribing information and SPC can be found on the landing page of the extranet site

28. Adapted from Worth PF. Pract Neurol. 2013; 0: 1-13. doi: 10.1136/practneurol-2012-000463. Prescribing information and SPC can be found on the landing page of the extranet site

29. Worth PF. Pract Neurol. 2013; 0: 1-13. doi: 10.1136/practneurol-2012- 000463. A decision-making algorithm for advanced therapies in Parkinson's Disease Prescribing information and SPC can be found on the landing page of the extranet site

30. Conclusions As Parkinson’s progresses, increasing complexity of conventional treatment may fail to control symptoms satisfactorily Advanced therapies can improve motor fluctuations and dyskinesias and improve quality of life Early identification of patients is vital – don’t let them miss the boat Each treatment has a distinct profile that must be matched to individual patients Prescribing information and SPC can be found on the landing page of the extranet site