Update on the Treatment of Parkinson s Disease. Neurotherapeutics for Rehab Professionals November 6 th, 2015

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1 Brent Bluett, DO Dr. Brent Bluett completed medical school at Touro Unviersity Nevada College of Osteopathic Medicine, neurology residency at the University of Texas Southwestern at Austin, and a Movement Disorders Fellowship at the University of California San Diego. He returns to the Las Vegas area as a Movement Disorders specialist at the Cleveland Clinic Nevada Lou Ruvo Center for Brain Health (CCLRCBH). His expertise is in Movement Disorders such as Parkinson s Disease, Atypical Parkinsonism (Progressive Supranuclear Palsy), Dystonia, Ataxia, and Tremors. Dr. Bluett is fellowship trained in therapeutic interventions such as Botulinum toxin injections and Deep Brain Programming Stimulation, and leads the Botulinum toxin for Dystonia clinic at the CCLRCBH. He recently completed the first large research study on predicting and preventing falls in Progressive Supranuclear Palsy, and intends to expand the findings to reduce falls in other Movement Disorders. His other research interests include transcranial direct-current stimulation to improve motor function in Parkinson s disease and Dystonia, and neuroimaging utilizing the cutting edge imaging modalities at the Lou Ruvo Center for Brain Health. Note: Dr. Bluett has no relationship which, in the context of his presentation, could be perceived as a potential conflict of interest.

2 Update on the Treatment of Parkinson s Disease Neurotherapeutics for Rehab Professionals November 6 th, 2015

3 Therapeutic principles of treatment

4 1) No proven protective/restorative effects with medications as of yet MAO-B inhibitors have shown promise in modifying disease progression Exercise reduces loss of dopamine neurons in MPTP lesioned rats Induces growth factors (GDNF, BDNF)

5 2) Encourage patients to remain active and mobile Decreased motivation, increased passivity in PD -> active exercise program may help PT/exercise useful in all stages of the disease Better motor performance seen in patients w/ PD who exercise intensely and regularly

6 3) Keep the patient functioning independently as long as possible Drugs help symptoms but don t stop disease progression 75% of patients have serious complications of Levodopa tx 5 Major responses > 5 years of Levodopa therapy: 1) Troublesome fluctuations (43%) 2) Smooth, good response (25%) 3) Troublesome dyskinesias (20%) 4) Total or substantial loss of efficacy (8%) 5) Toxicity at therapeutic/sub therapeutic dose (4%)

7 3) Keep the patient functioning independently as long as possible Levodopa therapy: Younger patients are more likely to develop motor fluctuations and dyskinesias Older patients are more likely to develop confusion, psychosis, sleep-wake alterations from medications

8 4) Individualize therapy Consider each patient s symptoms, degree of functional impairment, and expected risks/benefits of treatment agents Determine issues by asking the patient to list the specific symptoms that trouble them the most. Then attempt to treat the most troublesome symptoms This will maximize the patient s quality of life

9 Pharmacologic Treatment of Parkinson s Disease

10 Patient with Parkinson s Disease - OFF medication

11 Same patient ON medication

12 Therapeutic Options 1) MAO-B Inhibitors 2) Dopamine Agonists 3) Carbidopa-Levodopa 4) IPX-066 5) Duodopa 6) Botulinum Toxin injections 7) Deep Brain Stimulation

13 MAO-B Inhibitors

14 DATATOP trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism Selegiline (5mg PO bid) delayed symptomatic treatment by 9 months Helps avoid Levodopa induced motor complications

15 BLIND-DATE trial Subjects on Selegiline required lower dosage of levodopa Had slower rate of worsening of symptoms and signs of PD, and less freezing of gait

16 TEMPO and ADAGIO trials Rasagaline can reduce the rate of clinical worsening in patients with early PD TEMPO: 2mg Rasagaline had superior result > 1 mg ADAGIO: Only the 1mg dose was superior to placebo

17 Recommend start treatment in Early PD with MAO-Inihbitor <10mg/day Selegiline < 2mg/day Rasagiline

18 Dopamine Agonists

19 Oral: Ropinirole (Requip and Requip XL) Pramipexole (Mirapex and Mirapex ER) Transdermal: Rotigotine (Neupro) Dopamine Agonist monotherapy is rarely successful > 3 years

20 Nausea DA Agonist common side effects Orthostatic hypotension Common cause of falls Important to assess BP Supine, Sitting, Standing, Standing after 3 minutes Timed up and go *Advise caution when standing or sitting up Somnolence Ask pt s about sleep attacks, may require Modafinil Hallucinations

21 DA Agonist common side effects: Impulse Control Disorder Compulsive gambling, shopping, sexual behavior Impulsive patients may attempt to walk faster than they re capable of, or stand up too quickly Leg edema (later) Compression stockings Elevate feet above level of heart

22 Dopamine Agonist Withdrawal Syndrome (DAWS) Not relieved by Levodopa Symptoms: Anxiety, panic, agoraphobia, depression, diaphoresis, OH, fatigue, pain, drug cravings *Advise physician if patient showing signs Gradually reduce DA Agonist. Do not discontinue immediately. May need to restart DA Agonist at low dose

23 Carbidopa-Levodopa (Sinemet)

24 Sinemet IR 10/100, 25/100, 25/250 mg Start with 25/100 mg, increase by 25/100 mg q week until reach desired outcome Usually 25/100 mg tid Bradykinesia and Rigidity respond best Tremor may be more resistant Reasonable high dose of levodopa before concluding inefficacy = 2,000 mg/day

25 Sinemet CR: Useful as a first line drug in pts > 70 y/o Lowers peak plasma level, less drowsiness or confusion Pre-bedtime dose may increase nighttime mobility, but can have an excess delayed response Severe, sustained dyskinesias, less predictable response with CR

26 Nausea Carbidopa-Levodopa side effects and complications of therapy Orthostatic Hypotension Midodrine, Fludrocortisone (Florinef), Droxidopa (Northera) Supine hypertension Elevate head of bed 30 degrees Somnolence Hallucinations Dyskinesias Amantadine

27 Carbidopa-Levodopa side effects and complications of therapy Fluctuations: OFF vs. ON Duration of Levodopa dose becomes shorter as PD worsens Pharmacokinetic ½ life is 90 minutes Clinical ½ life: Stage 1: 262 minutes Stage 2: 142 minutes Stage 3: 54 minutes

28 Carbidopa-Levodopa side effects and complications of therapy Fluctuations: Entacapone COMT inhibitor, prolongs ½ life of Levodopa Increased risk of dyskinesias earlier on when used with Sinemet Sinemet CR Not shown to avoid fluctuations Better to use small, divided doses of Sinemet IR

29 IPX-066 (Rytary)

30 Contains immediate release and extended-release beads Dissolves in GI tract at varying rates Specific amount of Carbidopa and levodopa in a 1:4 ratio Carbidopa/Levodopa: 23.75mg/95mg 36.25mg/145mg 48.75mg/195mg 61.25mg/245mg Provides both initial and extended levodopa plasma concentrations

31 1 393 PD patients with > 2.5 hours off-time per day IPX066 (given 3-6 times a day) vs. Carbidopa/Levodopa IR Reduced off-time by 1.17 hours/day Final daily dose of IPX066 was approximately double that of Carbidopa/Levodopa IR Adverse events over 13 week period: 43% with IPX066 40% with Carbidopa/Levodopa IR

32 Conclusions: Many PD patients with motor fluctuations can be switched from Carbidopa-Levodopa IR to IPX066 with: Reduced dosing frequency Reduced off-time Improved functionality Improvement in some measures of quality of life

33 Conversion from Carbidopa-Levodopa IR to Rytary

34 Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopalevodopa (IPX066) with immediate-release carbidopalevodopa (Sinemet), sustained-release carbidopalevodopa (Sinemet CR), and carbidopa-levodopaentacapone (Stalevo) Hsu, A., Yao, H.-M., Gupta, S. and Modi, N. B. (2015), Journal of Clinical Pharma, 55: doi: /jcph.514

35 Study Conclusions Carbidopa-Levodopa IR: Reached peak concentrations (C max ) at 1 hour LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. Sinemet CR and Stalevo (Carbidopa-Levodopa-Entacapone): Reached peak concentration (C max ) at 1.5 hours LD concentrations were less than 10% of peak by 6.3 (Sinemet CR) and 7.5 hours (Stalevo) IPX066 (Rytary): Reached peak concentration (C max ) at 4.5 hours LD concentrations were less than 10% of peak by 10.1 hours

36 Anecdotal Clinical Observations of Rytary Decreases fluctuations Patient s don t get initial kick of Sinemet IR Less dyskinesias Takes time to convert dosing properly Take delayed onset and sustained benefit into account when assessing patients Determining if patient is OFF or ON may be more difficult

37 Levodopa/Carbidopa Intestinal Gel (LCIG) or Duodopa

38 Intrajejunal percutaneous gastrostomy tube LCIG provides continuous drug delivery in order to provide a stable plasma LD concentration Goal: continuously stimulate striatal dopamine receptors Non-oral route avoids fluctuations in absorption due to delayed gastric emptying and competition for GI uptake

39 Duodopa Pump

40 Clinical Indications for Duodopa: Advanced Parkinson s Disease Severe motor fluctuations and dyskinesias resistant to conventional therapy Satisfactory response to Levodopa Ability to tolerate surgery and have social support to handle postoperative care Contraindications to Duodopa: Pronounced dementia Medical contraindications to abdominal surgery

41 Anecdotal Clinical Observations of Duodopa Reserved for advanced PD patients Does help reduce fluctuations and dyskinesias Patients must initially come to clinic for full day to adjust bolus and maintenance doses Patients need caretakers to assist with administration Tube can become dislodged Requires coordination with GI specialist

42 Botulinum Toxin Injections

43 How Botox Works

44 Indications in Parkinson s Disease Dystonia Sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures Sialorrhea Excessive salivation and drooling Overproduction and reduced swallowing

45 Cervical Dystonia

46 Focal Foot Dystonia

47 Dystonia in Parkinson s Disease

48

49 Botulinum Toxin for Dystonia Focal Dystonia Standard dosage = Units Sialorrhea Standard dosage = 40 Units Clinical improvement generally begins within the first two weeks after injection Maximum clinical benefit at approximately six weeks post-injection. Most patients return to pre-treatment status by 3 months post-treatment.

50 Physical therapy program for cervical dystonia: a study of 20 cases Botulinum toxin (BTX) is the best therapeutic option in patients with cervical dystonia (CD) Physical therapy (PT) can be added to the treatment to achieve better results. Combination of: Motor Learning Exercises Kinesiotherapy Functional Electrical Stimulation of antagonist muscles Botox + PT group showed greater improvement than Botox alone in pain and disability

51 Special Considerations in Therapy for Dystonia Prolonged immobilization of a limb can cause a peripheral dystonia Botulinum toxin adjunctive therapies should focus on decreasing pain and improving functionality Monitor for excessive weakness, especially in patients who receive botulinum toxin in lower extremities Speech therapy important to monitor for dysphagia/dysarthria after botulinum toxin injections for cervical dystonia Important to manage patient expectations

52 Deep Brain Stimulation for Parkinson s Disease

53 Before and After DBS

54 How DBS works Non-destructive and reversible means of disrupting the abnormal function of thalamic and basal ganglia nuclei and their circuits Stimulation parameters are programmed non-invasively, postsurgery Adjustments made to deliver the appropriate level of stimulation Amplitude Frequency Pulse Width

55 FDA Indication for Parkinson s Disease Indicated for bilateral stimulation of the globus pallidus interna (Gpi) or the Subthalamic nucleus (STN) as an adjunctive therapy in reducing some of the symptoms of advanced, levodopa-responsive Parkinson s Disease that are not adequately controlled with medication Ventral intermedius nucleus (Vim) of the thalamus can be targeted to reduce tremor in PD

56 Inclusion criteria for DBS in Parkinson s Disease Idiopathic Parkinson s Disease Troublesome motor symptoms despite optimal pharmacologic treatment Intolerable side effects to antiparkinsonian medication Patient still has clear motor improvement with Levodopa Generally > 30% improvement in UPDRS III Motor exam ON vs. OFF

57 Exclusion criteria for DBS in Parkinson s Disease Significant medical conditions that prevent surgery Dementia Moderate to severe depression Age > 70 Levodopa-unresponsive gait and balance abnormalities Intellectual impairment

58 DBS Multidisciplinary Evaluation UPDRS III Motor examination both OFF and ON Levodopa Physical Therapy/Occupational Therapy/Speech Therapy Provide input regarding patient s overall status, potential areas of improvement, limitations, risks/benefits PT: Gait disability/tendency to fall OT: Manual dexterity, potential functional disorder? ST: Dysarthria, dysphagia, aphasia Neuropsychiatric evaluation MRI Brain Systemic comorbidities Social circumstances

59 Important considerations in DBS Gait unlikely to improve May worsen postural instability STN vs. GPI: STN: Greater benefits, greater risk Can cause disinhibition, personality changes, induce dyskinesias Therapists can be of great benefit in setting programming parameters Overstimulation can cause: Dysarthria (bilateral Gpi) Muscle contraction (Gpi) Dysequilibrium and gait ataxia (STN) Please advise physician responsible for DBS programming

60 Conclusions Therapists are vital to management of Parkinson s Disease Medications and surgery only go so far! Two most feared complications of PD: Falls Dysphagia Monitor for complications of medical/surgical therapy Team approach Communication between physician and therapist is key Respect each other s areas of expertise Encourage exercise Optimize patient s quality of life

61 References 1) Fahn S, Jankovic J, Hallett M. Principles and Practices of Movement Disorders 2011, Elsevier Saunders. 2) Robert Hauser, Ann Hsu, Sherron Kell, Alberto Espay, Kapil Sethi, Mark Stacy, William Ondo, Martin O Connell, Suneel Gupta, for the IPX066 Advance-PD investigators. Extended-release carbidopalevodopa (IPX066) compared with immediate-release carbidopalevodopa in patients with Parkinson s disease and motor fluctuations: a phase 3 randomised, double-blind trial Lancet Neurology, 2013:12: ) Hsu, A., Yao, H.-M., Gupta, S. and Modi, N. B. Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopalevodopa (Sinemet), sustained-release carbidopa-levodopa (Sinemet CR), and carbidopa-levodopa-entacapone (Stalevo). 2015, Journal of Clinical Pharma, 55: doi: /jcph.514