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” withouttime . 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

Entacapone With every ldopa Tolcapone Tid Monitor for hepatotoxicity

Fox et al. Move Disord 2018 Opicapone

. Peripheral COMT placebo Opicapone Opicapone inhibitor 25 50 . High potency, long N 135 125 147 duration % < 1 50.4 78 97 hour off p=0.04 p=0.009 . FDA approved in 2020 as time (Ontgentys®) % > 1 45 63 62 hour on p=0.004 p=0.006 . Phase 3 study completed time Total 59 104 111 . Maintained effect at 1 increase p=0.02 p=0.005 year in on . AE’s mild, most frequent time was dyskinesia Lees et al. JAMA Neurology 2017 Opicapone: Long term efficacy Pooled analysis: BIPARK1 BIPARK2 . 633 fluctuating PD . Opicapone 25, 50 mg qd . Double blind with open label follow up for 1 year

. Reduced off time, increased on time without troublesome dyskinesia

Ferreira et al. Eur J Neurol 2019 Istradefylline (Nourianz®)

. Adenosine A2A receptor antagonist . Variable results initially . FDA approved as adjunct 2019 for “off” time in PD based on DBPC studies . Approximately 1 hour less off time. . Improved motor symptoms . Dyskinesia most frequent AE

Sako et al. Sci Rep 2017 Istradefylline long term

. 308 fluctuating PD treated for 1 year . Open label . Istradefylline 20-40 mg/day

. Decrease in daily off up to 1 hour . Most frequent side effect nasopharyngitis (unrelated) and mild to moderate dyskinesia

Kondo et al. Clin Neuropharm 2015 On demand therapies

. For unpredictable off times  Stress related  Post prandial  End of dose  Delayed onset  Partial response/failed response

. Quick onset of action . Well tolerated . Easily administered

. Early morning off Subcutaneous Apomorphine “rescue”

. Response equal to levodopa

. Sudden “off” periods

. Subcutaneous injection  onset 7.5-10 mins  duration 60-120m Sublingual Apomorphine FDA approved 2020 (Kynmobi®)

. Bi layer film . Dissolves under the tongue into the circulation . Avoids GI delays . No first pass effect . Available in multiple dose strengths Sublingual Apomorphine

. DBPC study . 109 PD with 2 hours off and morning off . Maintained on usual regimen of PD meds . Used from 10-35 mg depending on optimal dose

Olanow et al. Lancet Neurol 2020 Sublingual apomorphine

. Adverse effects . Special considerations  Oropharyngeal irritation  Pretreat (31%); discontinuation trimethobenzamide 3 days 17%)  Drink water before  Nausea  Keep under tongue until  Somnolence dissolved  Orthostatic hypotension  Maximal 5 doses per day  Prolonged QT in 1 patient  ? Dyskinesia (not in this  Contraindicated with 5HT3 study) antagonists (ondansetron, etc. )

Olanow et al. Lancet Neurol 2020 Package insert Inhalational Levodopa :Inbrija® FDA approved 12/2018

. 4 week RCT . 86 fluctuating PD subjects . 2 doses per day . UPDRS part III improved in 10 minutes . 0.8 hours less off time daily . PGIC improvement in 72% CVT vs 46% placebo . No change in PFT’s

. Approved for intermittent “off” periods in PD up to 5 per day

LeWitt et al. Move Disord 2016 UPDRS part III Treatment of dyskinesia Amantadine mean dyskinesia score during placebo and amantadine IV infusions

Del Dotto et al. Move Disord 2001;16:515. Amantadine

. Effects in Parkinson disease  Modest benefit for the motor symptoms of PD  Reduce dopamine induced dyskinesias in PD  Doses 200-400mg in divided doses

 Caveat : secreted unchanged through kidney. Caution in renal insufficiency or failure

 Side effects  Anticholinergic, leg swelling, livedo reticularis, hallucinations ADS 5102 Amantadine Extended release (Gocovri®) EASE LID study FDA approved August 2017 (Adamas Pharmaceutical)

. DBRPC study  126 PD patients on levodopa randomized  2 half hour “on”times with troublesome dyskinesia (peak dose)  ADS-5102 at 274 mg dosed at bedtime  Primary outcome 12 weeks  Study continued to 24 weeks  Primary and secondary outcome measures:  Δ baseline of Unified Dyskinesia Rating Scale (UDysRS)  Hauser diaries Pahwa et al. JAMA Neurol 2017 ADS 5102

. Reduced dyskinesia . Reduced off time (0.9 hours) . ADS increased on time without troublesome dyskinesia (2.7 hours) . Adverse effects with ADS-5102  Visual hallucinations (21%), peripheral edema (21%) , dizziness, dry mouth, constipation, livedo reticularis (9.5%)  No impulse control disorder

. EASE-LID 3 with similar results

Pahwa et al. JAMA Neurol 2017 Oertel et al. Mov Disord 2017 Other agents considered for motor fluctuations/dyskinesia

 Subcutaneous apomorphine infusions  Zonisamide  Levetiracetam  Clozapine  Cannabis  Foliglurax  IPX203: new formulation of Rytary® NB1b-1817 or VY-AADC01

. NBIb-1817  investigational gene therapy product  deliver the AADC gene directly into the putamen  enable the putamen to produce the AADC enzyme  enhance the conversion of levodopa to dopamine  single administration.

. Restore 1 Trial in progress (Phase 2) Exercise

. Many types assessed . Benefits  Walking  Motor severity scores  Tai Chi  Functioning  Progressive resistance  Balance  Forced bicycle riding  Falls  Treadmill  Cognition  Dance  Strength  Etc.  Mood  Quality of life