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Therapy for Movement Disorders Cynthia Comella, MD, FAAN Rush University Medical Center Chicago, IL TREATMENT OF MOTOR SYMPTOMS IN PARKINSON DISEASE Disclosures . Compensation/honoraria for services as a consultant or an advisory committee member: Acadia, Aeon, Allergan, Inc; Impax Pharmaceuticals; Ipsen Biopharmaceuticals, Inc; Medtronic Inc.; Merz Pharmaceuticals; Neurocrine. Royalties: Cambridge, Humana Press; Wolters Kluwer Objectives Treatment of PD . Available treatments for motor PD Treatment of motor symptoms Treatment of motor complications Motor fluctuations Dyskinesia . Overview new therapies in clinical trial Not my objectives Before I came here I was confused about this subject. Having listened to your lecture I am still confused. But on a higher level. Enrico Fermi PD motor symptoms: Therapeutic targets Oertel W, Shulz JB. J Neurochem 2016 . No effective neuroprotective agent . Monotherapy (Efficacious) Levodopa Dopamine agonists: (pramipexole, ropinirole, rotigotine) MAO-B inhibitors: (selegiline, rasagiline) Amantadine (likely) . Motor fluctuations (Efficacious) Efficacious: Dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine) Levodopa gel intestinal infusions COMT inhibitors (entacapone, tolcapone, opicapone) MAO-B inhibitors (rasagiline, safinamide) Zonisamide Bilateral STN and GPi stimulation . Dyskinesia (Efficacious) Intestinal infusions Amantadine Bilateral STN and GPi stimulation clozapine Fox et al. Mov Disord March 2018 Modest benefit . MAO-B inhibitors (selegiline, rasagiline, safinamide) Modest benefit Not neuroprotective Used for motor fluctuations (extends half life LD) . Anticholinergics May help tremor rigidity, not bradykinesia Many side effects Largely reserved for young subjects . Amantadine Most used for treatment of dyskinesia affects dopamine, acetylcholine and glutamate Mild improvement for PD symptoms Renal clearance (care with elderly or kidney disease) Levodopa . Gold standard for 50 years . Efficacious as monotherapy treatment for PD symptoms . No evidence for enhanced disease progression Levodopa: Common misconceptions of patients . If I take levodopa now, I will develop tolerance to it in the future . I am afraid to start levodopa because I will use up the “good time” . I should only take medication when I find it impossible to carry out my life . Levodopa will cause faster progression of my PD Levodopa in early, untreated PD ELDOPA study PSG. NEJM 2004; 351:2498-2508 . 445 with PD diagnosis within 2 years . Untreated . Randomized: Oral levodopa 100 tid for 80 weeks Placebo tid for 40 weeks then levodopa 100 tid for 40 week Primary outcome was between-group differences in change from baseline to week 80 on total UPDRS Verschuur et al. NEJM 2019 Results Verschuur et al. NEJM 2019 Conclusions . No difference Disease progression Rate of dyskinesia Levodopa-related dyskinesia . Levodopa treatment at 25/100 tid had no detrimental effect on patients with early PD Verschuur et al. NEJM 2019 Dopamine agonists Half Life in hours Pramipexole (Mirapex®) 8 hours (tid) Pramipexole ER 12 hours (1ce day) Ropinirole (Requip®) 6 hours (tid) Ropinirole XL 47 hours (1ce daily) Rotigotine patch (Neupro®) 5 hours: terminal half life Agonist efficacious as initial therapy for symptoms and to delay motor fluctuations ropinirole Rascol et al. NEJM 2000;342(20):1484-91 pramipexole Halloway et al. Arch Neurol 2004 Pramipexole vs Levodopa as Initial Treatment for Parkinson Disease A 4-Year Randomized Controlled Trial Arch Neurol. 2004;61(7):1044-1053. doi:10.1001/archneur.61.7.1044 Halloway et al. Arch Neurol 2004 Dopaminergic agents: side effects . Levodopa > DA . Dopamine agonists > agonists levodopa Nausea Impulse control disorders Dyskinesia Excessive daytime sleepiness Motor fluctuations Hallucinations Dopamine Orthostatic hypotension dysregulation Pedal edema with erythema (addiction) PSG Arch Neurol 2004 Initial treatment Direct Dopamine Agonist vs levodopa . Dopamine agonists Less dyskinesia and motor fluctuations in the first 5 years with agonist More side effects . Levodopa Better efficacy Fewer side effects No evidence for neurotoxicity Fox et al. Move disord 2018 Hauser et al. Move Disord 2007 Katzenschlager R et al Neurology 2008 Shannon K. Nat Clin Pract 2008 Initial monotherapy with dopamine agonists is not superior to initial monotherapy with levodopa Levodopa Dopamine agonists Oertel W, Schulz J. J Neurochem 2016 Chaudhuri et al. Mov Disordr 2018 Chaudhuri et al. Mov Disord 2018 Risk factors • Dyskinesia . Motor fluctations • Lower age of onset Lower age of onset • Higher dose levodopa Higher dose levodopa • Treatment in North Higher UPDRS part II America more than North America > Europe Europe Female gender • Lower weight More severe disease • Female gender Olanow CW, Stocchi F. ov Disord 2018 Available preparations of carbidopa/levodopa . Immediate release (Sinemet ®) . Orally dissolving (Parcopa®) . Controlled release (Sinemet CR®) . Combination with entacapone (Stalevo®) . IR/CR (Rytary®) . Levodopa intestinal gel (Duopa ®) Available preparations of carbidopa levodopa . There does not appear to be an advantage of one preparation of carbidopa levodopa over another in early PD in delaying motor fluctuations Stride PD study (carbidopa levodopa with and without entacapone) IR carbidopa/ levodopa to CR Stocchi et al. Ann Neurol 2010 Koller WC et al. Neurology 1999 Extended release levodopa (IPX066, Rytary®, Impax) . Combines immediate release levodopa and extended release levodopa . Capsules containing beads of both formulations . Rapid onset of action (IR) with extended effects from controlled release (ER) . Doubles the duration of effect of regular levodopa . Tartaric acid incipient to promote absorption of levodopa in the more alkaline gut. Margolesky and Singer. Adv Neurol Disord 2018 Extended-release carbidopa-levodopa (IPX066) compared with immediate- release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial Caveat: Dose of levodopa was 45% higher in the IPX066 group Hauser et al, 2013 , Rytary ® : advantages-disadvantages Advantages Disadvantages . Fewer doses during the . More pills at a single dose day . Switching from IR to . change levodopa dose in Rytary smaller increments: More . Brand name so may be control of motor more expensive symptoms vs dyskinesia? . No known advantage . Nighttime dosing: less when initiating therapy, symptoms during night, only in patients with improvement in sleep motor fluctuations due to PD symptoms? IPX203: Impax and Amneal . Reformulation of IPX066 (Rytary®) . Longer acting (up to 7-8 hours) . Phase 2 results positive . Phase 3 study in 510 PD patients with motor fluctuations in progress Modi et al. Clin Neuropharm 2019 Levodopa gel intrajejunal infusions Duopa ® . Continuous release during the day . Delivered directly to small intestine where levodopa absorbed . No issues with slowed GI transit Levodopa‐carbidopaintestinal gel (Duopa®) in advanced Parkinson's disease 12‐month, open‐label results Fernandez et al. Mov Disord 2015 Amjad et al. Adv Ther 2019 Duopa® (levodopa gel) . Approximately $60,000 per year Coverage and reimbursement support . Complications in 47% 35% with device insertion 31 % abdominal pain 17% nausea 15% post-operative wound infection 40% levodopa associated peripheral neuropathy increased homocysteine; reduced vitamin B12; increased methylmalonic acid; and reduced vitamin B6. Fernandez et al. Mov Disord 2015 Romagnolo et al. Mov Dis Clin Prac 2018 In the pipeline: ND0612 (Neuroderm) . Continuous subcutaneous infusion of levodopa/carbidopa . Stable plasma levodopa levels . Reduction in off time without troublesome dyskinesia . Limited by dosing of levodopa (900 mg per day) Giladi et al. Mov Disord 2015 (abstract) Kieburtz et al. Mov Disord 2016 Olanow, Stocchi Mov Disord 2017 In the pipeline: The Accordion pill AP09004 (Intec Pharma) . Gastric retention capsule . Multiple layers combining immediate and slow release form of l-dopa . Plasma half-life of 5-7 hours . TID dosing . Phase 3 study underway comparing to IR levodopa . Open label extension Levodopa accordion pill Intecpharma.com 2018 Lewitt et al. Parkinsonism Rel Dis 2019 Prolong effect of levodopa . COMT inhibition . MAO B inhibition . Provides 1-2 hours of increased time with effective treatment when combined with levodopa Treatment of motor fluctuations MAO-B inhibition selegiline rasagiline safinamide Fox et al. Move Disord 2018 MAO B inhibitors . Selegiline Metabolized to l-amphetamine Mild reduction in OFF time for 1-1.5 hours Twice a day Extensive first pass metabolism . Rasagiline No amphetamine metabolites Once a day intake Reduced “off” time by 1.2 hours Golbe, Neurology 1989;8:1109-1111 Olanow CW et al. N Engl J Med 2009 Safinamide (Xadago®) Motor fluctuations (Newron Pharmaceuticals) . Water-soluble . Potent, highly selective reversible MAO-B inhibitor . Blocks voltage dependent Na and Ca channels . Reduces neuronal glutamate release Safinamide (Xadago®) FDA approved 3/2017 . Potent, highly selective reversible MAO-B inhibitor . Blocks voltage dependent Na and Ca channels . Reduces neuronal glutamate release . DB-PC-randomized . 549 fluctuating PD . Safinamide 100mg as tolerated “on” time without troublesome dyskinesia troublesome “on” time without . Daily “on” time at 24 weeks increased by 0.8 hours . Most frequent AE was modest increase in dyskinesia Schapira et al. JAMA neurol 2017 Treatment of motor fluctuations COMT inhibition
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