Update in the Management of Parkinson s Disease

Update in the Management of Parkinson s Disease What s standard? What s new? What s coming? Bruno V. Gallo, M.D. Assistant Professor of Neurology, FIU Wertheim College of Medicine Director, Parkinson & Neuromodulatoin Center Baptist Health, Miami Florida Disclosures: I am actively a consultant for the following: Cyberonics, Inc. Teva Pharmaceuticals St. Jude Medical, Inc. (dba Abbott Labs) Surgimon, LLC ONS, Inc. I am a member of the following speakers bureau: TEVA Pharmaceuticals Sunovion Pharmaceuticals I have received Fellowship and/or Research Grants: Medtronic International Pfizer Pharmaceuticals Glaxo-SmithKline St. Jude Medical, Inc. The gold standard since 1969 Levodopa 1969 Carbidopa / levodopa 1972 Carbidopa / levodopa controlled release 1992 Carbidopa / levodopa/entacapone 1996 Carbidopa and levodopa extended release capsules 2015 Levodopa intestinal gel 2016 1

Motor Fluctuations Symptoms adequately controlled ( on time ) Wearing off period Symptoms not adequately controlled ( off time ) PD Medication PD Medication PD Medication Time Typical Clinical Pattern of Wearing Off Adapted from Hauser RA. Geriatrics. 2006;61:14-20. Development of Motor Complications with Time on Levodopa double edged sword % Patients with Motor Complications 100 75 50 25 0 40% by 5 yrs 1 2 3 4 5 6 7 8 9 Time from Initiation of Therapy (years) 92% by 10 yrs 10 Adapted from Schrag A, et al. Mov Disord. 1998;13:885-94. Management of Parkinson s Disease? Considerations Age Cognitive function Comorbidity Dopamine agonists Parkinson s disease Nonpharmacologic Educate Support Exercise Nutrition Yes Olanow et al. Neurology. 2001;56(suppl 5):S1-S88. Dopamine agonist + Levodopa (+/-COMT inhibitor) Add COMT inhibitor Motor complications Pharmacologic Neuroprotection?Selegiline Functional impairment See section on control of motor complications No Continue to monitor Levodopa (+/- COMT inhibitor) Unacceptable control with medical therapies Consider surgery 2

Sites of Action of Parkinson s Disease Drugs selegiline/rasagiline MAO-B (breaks down dopamine) DDCI Levodopa COMT inhibitor Dopamine agonists Dopamine 3-OMD Therapy for Advanced Parkinson s Disease Dyskinesias Wearing off Non-motor symptoms Decrease levodopa dose Add dopamine agonist Amantadine Smaller, more frequent doses of levodopa or CR Add COMT inhibitor Add MAO-B inhibitor Add dopamine agonist Add amantadine Decrease doses of or discontinue offending medications Address specific problems with appropriate therapy Adapted from Waters C. Diagnosis and Management of Parkinson s Disease. 2006. Intestinal Infusion of Levodopa Continuous Therapy Levodopa/carbidopa oral Levodopa infusion 6 78.2%* 4 3 75%* 3 2 1 0 Hours OFF time *P <.0001 0 Dyskinesia score Stocchi F, et al. Arch Neurol. 2005;62:905-10. 3

Levodopa (µg/ml) 11/1/2018 Intestinal Infusion of Levodopa Continuous Therapy Response to Chronic Levodopa Therapy A B C 1 2 3 100 200 300 Time (minutes) 100 200 300 Time (minutes) Dyskinesia Good ('on') response Poor ('off ) response 100 200 300 Time (minutes) Chronic levodopa response is a narrowing of the therapeutic window. (A) Beginning of treatment. (B) Patient starts to experience motor complications. (C) Patient experiences severe motor complications. Adapted from Olanow CW, et al. Nat Clin Practice Neurol. 2006;2:382-92. Motor Fluctuation: Wearing Off Wearing off End-of-dose effect Most common motor fluctuation Possible treatment options Switch to sustained release carbidopa/levodopa Increase frequency of levodopa/carbidopa dosing Add rasagiline Add entacapone Consider pramipexole, ropinirole, tolcapone May consider selegiline or zydis selegiline Waters C. Diagnosis and Management of Parkinson s Disease. 2006. 4

AAN Recommendations for Therapy for Off Time Entacapone and rasagiline should be offered to reduce off time (Level A). Pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Use tolcapone with caution (requires monitoring). Apomorphine and selegiline may be considered to reduce off time (Level C). Insufficient evidence to recommend one agent over another Pahwa R, et al. Neurology. 2006;66:983-95. MAO-B Inhibitors Role in Advanced PD Selegiline Selegiline disintegrating Rasagiline Insufficient evidence that monotherapy prevents clinical progression or that adjunctive therapy prevents fluctuations Indicated as adjunctive therapy Orally disintegrating tablet Reduced amphetamine-like metabolites Indicated as adjunctive therapy 2nd-generation Some neuroprotective properties seen in animal studies Indicated as adjunctive therapy Azilect PI; Goetz CG, et al. Mov Disord. 2005;20:523-39; Olanow CW, et al. Neurology. 2001;56(Suppl 5):S1 S88; Selegiline PI; Zelapar PI. Offer Rasagiline to Reduce Off Time Percentage Decreases in Off Time with Rasagiline 1.8 h 29% 1 23% 1 1.41 h 21% 2 1.18 h 1.0 mg P<.001 vs PL 0.5 mg P=.02 1.0 mg P=.0001 Parkinson Study Group. Arch Neurol. 2005;62:241-8; Rascol O, et al. Lancet. 2005;365:947-54. 5

Carbidopa/Levodopa + COMT Inhibitor Role in PD Always given with levodopa Prolongs levodopa half-life; increases its transport to the brain; raises dopamine levels Reduces levodopa dosage Reduces off time May delay dyskinesias For idiopathic PD with signs and symptoms of end-of-dose wearing off May produce motor complications earlier Hauser RA, et al. Parkinson s Disease Questions and Answers. 2003; Olanow CW, et al. Neurology. 2001;56(Suppl 5):S1 S88; Stalevo PI; Waters C. Diagnosis and Management of Parkinson s Disease. 2006. Offer Entacapone to Reduce Off Time Rinne et al. ON time OFF time Levodopa dose Rascol et al. ON time OFF time 13% p<.01 22% p<.001 102 mg/d p<.01 9% p =.0005 21% p<.0001 Rascol O, et al. Lancet. 2005;365:947-54; Rinne UK, et al. Neurology. 1998;51:1309-14. Consider Pramipexole to Reduce Off Time Lieberman et al. Guttman et al. OFF time decrease Levodopa dose OFF time decrease 7% P =.0006 5% P =.0001 3% P =.007 15% 31% 27% Placebo Pramipexole Guttman M, et al. Neurology. 1997;49:1060-5; Lieberman A, et al. Neurology. 1997;49:162-8. 6

Consider Ropinirole to Reduce Off Time Rascol et al. OFF time decrease Lieberman et al. OFF time decrease Levodopa dose 4% P =.08 13% P =.003 6% P <.001 23% 31% Placebo Ropinirole 35% Lieberman A, et al. Neurology. 1998;51:1057-62; Rascol O, et al. Clin Neuropharmacol. 1996;19:234-45. Consider Tolcapone to Reduce Off Time Study Decrease Off time 100 mg 200 mg Placebo Mean levodopa dose P value Rajput 32% 48% 20% 200 mg <.01 Baas 31.5% 26.2% 10.5% 109 mg (P<.05) <.01 Baas H, et al. J Neurol Neurosurg Psychiatry. 1997;63:421-8; Rajput AH, et al. Neurology. 1997;49:1066-71. Potential Use of Apomorphine or Selegiline to Reduce Off Time Apomorphine vs Placebo 1 34% (2 h) off time vs 0% placebo (p = 0.02) Mean inpatient UPDRS motor scores 62% and 1%, respectively (p <.001) Selegiline vs Placebo 2 Mean hourly self-assessment of gait improved in 56% vs 30.4% placebo Mean hourly overall symptom control improved in 58% vs 26.1% placebo (p < 0.01) Mean daily levodopa dosage 17% vs 7% placebo Oral disintegrating selegiline vs Placebo 3 32% (2.2 h) off time vs 9% (0.6 h) placebo (p = 0.001) 20% (1.8 h) on vs 5% (0.4 h) placebo (p = 0.006) Dewey RB, et al. Arch Neurol. 2001;58:1385-92; Golbe LI, et al. Clin Neuropharmacol. 1988;11:45-55; Waters CH, et al. Mov Disord. 2004;19:426-32. 7

Potential Use of Apomorphine injectable Gallo BV Motor Fluctuation: On/Off On/Off phenomenon Sudden and unpredictable Results from shifts between undertreated & overtreated states Difficult to treat Possible treatment options Change to liquefied carbidopa/levodopa (small doses throughout the day) requires highly motivated patient solution made daily Add dopamine agonist Increase the levodopa dose? Risks increased dyskinesias Waters C. Diagnosis and Management of Parkinson s Disease. 2006. Motor Fluctuation: Freezing Freezing episode Possible treatment options Occurs during off state and on state Off -state freezing control levodopa off-time On -state freezing does not respond to dopaminergic therapy Increase levodopa/carbidopa dose Add dopamine agonist Add selegiline Reduce medication dose (risks wearing off) Nonpharmacologic techniques (auditory, visual, proprioceptive cues) Waters C. Diagnosis and Management of Parkinson s Disease. 2006. 8

Motor Complications: Levodopa-Related Dyskinesias Peak-dose dyskinesia Diphasic dyskinesia Off dystonia (wearing off/early morning) Myoclonus (awake, during sleep) Akathisia (wearing off, peak-dose) Respiratory dyskinesia/dysregulation Punding Adapted from Waters C. Diagnosis and Management of Parkinson s Disease. 2006. Potential of Amantadine to Reduce Dyskinesia Antiviral with antiparkinson effects Rapid, short-acting 45% total UPDRS dyskinesia score Antidyskinetic effects last <8 months May be considered to reduce dyskinesia Olanow CW, et al. Neurology. 2001;56(Suppl 5):S1 S88; Thomas A, et al. J Neurol Neurosurg Psychiatry. 2004;75:141-3; Waters C. Diagnosis and Management of Parkinson s Disease. 2006. Peak-Dose Dyskinesia Peak-dose dyskinesia Possible therapeutic options Most common type Occurs at the time of peak plasma levels and maximal levodopa benefit Reduce individual levodopa dose (risks more severe off state) more frequent, lower dosages Substitute IR for CR levodopa Early morning akinesia add IR to CR first thing upon awakening Add COMT inhibitor, dopamine agonist, amantadine Olanow CW, et al. Neurology. 2001;56(Suppl 5):S1-S88; Waters C. Diagnosis and Management of Parkinson s Disease. 2006. 9

Diphasic Dyskinesia Diphasic dyskinesia Less common affects ~15 20% of patients Occurs with rising or falling plasma levels beginning or end of levodopa response cycle Possible therapeutic options Substitute IR for CR levodopa Increase dopamine agonist dose Restrict levodopa to several early and/or midday doses Olanow CW, et al. Neurology. 2001;56(Suppl 5):S1-S88. Dystonia Dystonia Occurs as levodopa levels are rising or falling Most common as a wearing-off effect in the off state Painful, fixed postures predominantly affecting distal extremities includes morning or nocturnal painful foot cramps Possible therapeutic options Bedtime dose of CR levodopa Early morning levodopa Nocturnal dopamine agonist Olanow CW, et al. Neurology. 2001;56(Suppl 5):S1-S88. Continuous Therapy Approach for Motor Complications More physiologic stimulation of brain dopaminergic receptors Reduced risk of motor complications Therapeutic strategies: Subcutaneous apomorphine Continuous infusion of levodopa (intestinal gel) Long-acting dopamine agonists (CR & ER forms) Transdermal rotigotine patch Hutton JT, et al. Mov Disord. 2001;16:459-63; Metman LV, et al. Clin Neuropharmacol. 2001;24:163-9; Olanow CW, et al. Nat Clin Pract Neurol. 2006;2:382-92; Pahwa R, et al. Neurology. 2007;68:1108-15. 10

Apomorphine Continuous Therapy Levodopa dose decrease OFF time decrease (based on patient diary) 2.4 h 38% 55% Katzenschlager R, et al. Mov Disord. 2005;20:151-7. Rotigotine Patch Continuous Therapy OFF time Responder rate* 40 cm 2 60 cm 2 40 cm 2 60 cm 2 0.9 h 34% 2.7 h P<.001 Placebo 2.1 h P=.003 Rotigotine 57% 55% *p <.001 LeWitt PA, et al. World Congress of Neurology, 2005. Rotigotine Patch Continuous Therapy vs Pramipexole OFF time 2.44 h 2.82 h 0.88 h* ON time without dyskinesia 2.8 h 2.7 h 1.4 h *P<.001 rotigotine vs placebo Pramipexole Rotigotine Placebo Powew W, et al. EFNS, 2006. 11

ropinirole CR / pramipexole ER New formulations of dopamine agonists Double-blind, placebo-controlled, 24-week studies Primary outcome measure reduction in daily "off" time Mean reduction in daily levodopa of 278 mg Mean reduction in daily "off" time of 2.1 hours vs 0.3 hours with placebo Secondary outcome measures significantly improved 42% responders vs 14% placebo on CGI-I scale (p <.001) 52% responders vs 20% placebo based on change in off time and levodopa dose ( 20% reduction; p <.001) Surgical Therapy: Goals and Criteria for Patient Selection Goals: Reduce abnormal neuronal activity Restore dopaminergic tone Not simple, widespread effects distant from stimulation Consider surgical treatment in a patient: with uncontrolled, disabling dyskinesias with significant motor fluctuations and/or disabling tremor despite optimal medical management long-lasting benefit from antiparkinson medications Good medical condition without contraindications to surgery without cognitive deficits, includes untreated existing depression Gallo BV Surgical Therapy: Ablative Procedures/Stimulation Ablative Thalamotomy Pallidotomy Deep-brain stimulation reduces off time; increases on time without dyskinesias; reduces levodopa dose; improves tremor Can never make you better than your best medicated on time, but can give you more on time. I feel it s better to best medical therapy, and it has been shown in clinical trials Gallo BV 12

Deep Brain Stimulation: Advantages No destruction of brain tissue Can adjust stimulus parameters Can perform bilateral operations Disadvantages Implanted foreign body, risk of infection Battery replacement / Cost of equipment Time & effort needed for programming DBS of the STN for PD No. of Follow-Up Main Outcome Reduction Daily Investigator (Year) Patients (Months) (%)* Levodopa Dose Kumar et al (1998) 10 6-18 54 NA Limousin et al (1998) 24 12 5 12 24 26 60 50 Burchiel et al (1999) 5 12 44 51 Moro et al (1999) 7 16 42 65 Bejjani et al (2000) 10 6 62 62 Houeto et al (2000) 23 11 6 12 67 61 Molinuevo et al (2000) Rodriguez et al (2000) 15 6 66 80.4 15 9 12 36 74 61 55 38 *Percentage reduction in UPDRS III, scores taken in the on stim/off med condition compared with off med at baseline. Results maintained, data not specific. Three patients stopped taking levodopa. Eight patients stopped taking levodopa. The near future of medications: Coming soon. Accordion Pill (levodopa) The new accordion pill is under investigation. There was success in the Phase II clinical trials. Briefly this consists of a unique gastro retentive formulation that is made of biodegradable films. It is folded up to look like an accordion and upon reaching the stomach the capsule dissolves and the accordion pill unfolds and is retained in the stomach for up to 12 hours. It slowly releases the drug in a controlled manner towards the upper part of the gastrointestinal tract. Gallo BV 13

The near future of medications: Coming soon. Inhaled Levodopa for the treatment of PD off episodes called: CVT-301 CVT-301 is currently in development in Phase 2 and 3 clinical trials as an inhaled form of levodopa. The trials just completed in the EU. It is indicated as a rescue medicine for patients experiencing a lot of off times. It is a self administered inhaled therapy. The early trials were funded by a grant from the MJF Foundation. It will be a nice addition to our arsenal of therapies for patients who can use it properly. Gallo BV The near future of medications: Coming soon. APL-130277 Apomorphine is not new to PD and some patients may have used the subcutaneous injection. What is unique here is that APL-130277 is in development as a sublingual (under the tongue) rescue medication. The good news is that in the clinical trials it seemed to work as fast as the injections. After completing the current study, APL-130277 will complete the other necessary clinical studies to support its approval by the FDA. These studies, performed in the United States, include people who have Parkinson s disease who suffer from off episodes. These studies are completed for APL-130277 and the FDA approval should appear in mid to late 2019. Gallo BV Surgical Therapy - Neurorestorative: coming soon Fetal & stem cell, fibroblast pleuripotential transplantation? Neurotrophic factor infusions? Gene therapy? Gallo BV 14