Dopamine Agonist Initiating Therapy in Early PD Patients: When Do We Initiate Therapy?

Parkinson’s disease : spectrum of motor manifestations in early and advanced PD

TANYA SIMUNI, MD AC NIELSEN PROFESSOR OF NEUROLOGY PARKINSON ’ S DISEASE AND MOVEMENT DISORDERS CENTER NORTHWESTERN UNIVERSITY Disclosures

 Dr. Simuni has served as a consultant Acadia, Abbvie, Adamas, Allergan, Accorda, Amneal, Denali, Neurocrine, Neuroderm, Revance, Sanofi, Sinopia, Sunovion, Takeda, Voyager , the Parkinson Foundation, and the Michael J. Fox Foundation for Parkinson’s Research;  Dr Simuni is on the Scientific advisory board for Sanofi, Neuroderm, MJFF.  Dr. Simuni has received research funding from the NINDS, MJFF, PF, Biogen Neuroderm, Sanofi. Case study

 52 y.o. right handed executive  Recently diagnosed with PD  No therapy at present  C/o of mild right arm tremor but no impact on ADLs

What is the diagnosis ? What is your Dx certainty ? Treatment decisions ? Parkinson’s Disease Clinical Diagnosis

UK Brain Bank Diagnostic criteria (Hughes 1992)  Step I- Diagnosis of parkinsonian syndrome  Step II- Exclusion criteria for PD  Symptomatic parkinsonism  Oculogyric crises, Sustained remission  Supranuclear gaze palsy, Early severe autonomic dysfunction, Cerebellar signs, Early severe dementia  Poor response to large doses of levodopa

MDS Clinical Diagnostic criteria MDJ 2015 PD:Clinical diagnosis (cont)

 Step III- Supportive features (3 or >)  Unilateral onset  Rest tremor  Progressive signs and symptoms, asymmetry of signs  Excellent early response to levodopa  Levodopa-induced dyskinesias  Clinical course >10 years  Diagnostic accuracy  1992: 100 cases-76%/ Retrospectively- 82% ( Hughes JNNP)  2001: 100 cases- 90% ( Hughes, Neurology)

MDS PD clinical Dx criteria 2015 MDS PD clinical Dx criteria 2015

Pathology Normal PD

Courtesy of Kapil D. Sethi, MD For Consultant Use Only Histology of PD Showing Lewy Body

For Consultant Use Only

c PD related pathology Stages of the development (Braak)

H. Braak et al Cell tissue research 2004 Parkinsonism Classification  Idiopathic PD ( 75%)  Symptomatic parkinsonism  Neurodegenerative diseases  Other disorders with parkinsonian signs Symptomatic Parkinsonism

• Drug- induced • Toxin- induced (Mn, CO, MPTP) • Metabolic disorders • Vascular parkinsonism • Postencephalitic • Posttraumatic Neurodegenerative Ds

 Progressive Supranuclear Palsy  Multiple System Atrophy  Cortical - Basal Syndrome  Diffuse Lewy body Disease  ALS – Parkinsonism - Dementia / of Guam  Alzheimer’s with extrapyramidal signs  Rigid variant of Huntington’s Disease  NBIA (former Hallevorden- Spatz Disease) Parkinson’s Disease Diagnostic work up

 Clinical diagnosis!!!  History!  Ancillary tests  MRI- nondiagnostic  SPECT- Dopamine transporter uptake scans DAT scan PD: Clinical spectrum 95% drug 5% drug development for PD development for PD

Motor symptoms Non-motor  Bradykinesia symptoms Sleep dysfunction  Neuropsychiatric Rigidity •Disrupted sleep  Tremor  Dementia  Depression •Primary sleep disorders  Postural instability  Psychosis •RLS, OSA  Anxiety  Apathy •Parasomnias  Anhedonia •RBD  ICDs •Somnolence Autonomic dysfunction  Orthostatic hypotension Sensory symptoms  Bowel •Olfactory dysfunction  Bladder •Visual symptoms  Sexual dysfunction  Hyperhydrosis •Pain Other symptoms  Fatigue  Weight loss  Weight gait (meds induced )

Simuni, Sethi Annal Neurol 2008 PD Clinical Course of PD

Kalia LV, Lang AE et al, Lancet 2015 PD: Advanced manifestations and motor complications

Advanced manifestations Motor complications

 Overal increase in disability  Motor fluctuations  ON-OFF  Lesss robust response to Tx  Dose failure  Posture  Delayed time to ON  Postural instability/ falls  Dyskinesia  Drug induced involuntary movements  Freezing of gait  Mostly peak dyskinesia  Dysphagia  OFF dystonia  Diurnal dyskinesia  Freezing of gait ( types )  OFF  Peak ON  Medications refractory FOG  You have to map these out ! Concept of Motor Fluctuations and Dyskinesia in PD

Key factors in development of motor complications

1. The degree of presynaptic dopamine denervation 2. Intermittent doses of dopaminergic therapy with a short half life

Obeso JA et al. Neurology. 2000;55:S13-S20. 20 Concept of Motor Fluctuations and Dyskinesia in PD

Physiologic motor functioning

• Chronic intermittent stimulation of dopaminergic • CDS reverses these complications receptors leads to motor complications • Pharmacotherapeutic options that enable CDS may facilitate prophylactic and palliative benefits

Chase TN. Drugs. 1998;55 (Suppl 1):1-9. Swanson G et al (eds.). Basal Ganglia, Parkinson’s Disease and Levodopa Therapy (suppl to Trends Neurosci). 2000.21 22 Management of PD motor disability Treatment of PD

Diagnosis of PD

Neuroprotective Tx clinical trials Monitor Anticholinergics Amantadine MAO-B inhibiotors Functional impairment No

Dopaminergic Tx

Levodopa(Sinemet*) Dopamine agonist Initiating therapy in Early PD patients: When do we initiate therapy?

 Optimal timing for onset of therapy has not been clearly defined  General rule of thumb: once parkinsonian signs and symptoms start to impact a patient’s life, therapy should be initiated  Treatment is tailored to the individual Treatment Options

Pharmacologic therapy Nonpharmacologic therapy Surgical therapy

Levodopa Education Deep brain stimulation Infusion therapies MAO-B inhibitors Exercise

COMT inhibitors Nutrition

Dopamine Support services agonists

Anticholinergics

Amantadine

A2A antagonists Sites of Action of PD Drugs Blood-brain barrier Periphery Neuron Brain

COMT 3-OMD inhibitors

L-DOPA L-DOPA MAO-B AADC inhibitors Carbidopa DOPAC DA DA DA DA DA DA DA COMT 3-MT inhibitor* *Only tolcapone inhibits COMT in brain. Dopamine receptors Dopamine L-DOPA = levodopa AADC = aromatic acid decarboxylase 3-OMD = 3-O-methyldopa DOPAC = dihydroxyphenylacetic acid agonists DA = dopamine 3-MT = 3-methoxytyramine Chaudhuri KR and Fung VSC. Fast Facts: Parkinson’s Disease 4th Edition. 2016; Health Press Limited Currently Approved Monotherapy for PD

CLASS AGENT Rasagiline MAO-B inhibitor Selegiline*

Immediate release Carbidopa/Levodopa Controlled release

Pramipexole IR Pramipexole ER Dopamine agonists Ropinirole IR Ropinirole XL Rotigotine patch

Amantadine

*Used no approval AAN Practice Parameters 2002 guideline. Reaffirmed 2005. Classes of drugs for symptomatic

therapy of PD motor28 manifestations

 Dopamine replacement Tx  Dopamine agonists

potency potency  Amantadine  COMT inhibitors

 MAO-B antagonists Increasing  A2A antagonists  Anticholinergics Simplify medications as disease progresses Treatment of PD 29

Symptomatic Therapy

Dopaminergic Tx

Levodopa Dopamine agonist Current Treatment Options for PD Adjunctive Drug Class Drug Monotherapy Therapya Dopamine precursor Carbidopa/levodopa ER, X CR, Rytary®, Duopa® MAO-B inhibitors Rasagiline X X Selegiline X X

Safinamide X Dopamine agonists Apomorphine X Pramipexole,Pramipexole X X ER X X RopiniroleRopinirole XL X X Rotigotine (Transdermal) X X

COMT inhibitors Entacapone X Tolcapone Antiglutamatergic Amantadine ER, X X Gocovry® Anticholinergicb Benztropine, biperiden, X COMT=catechol-O-methyltransferasetrihexyphenidyl; ER/XL=extended release; MAO-B=monoamine oxidase type B aAdjunctive therapy with levodopa.b Not recommended in elderly patients A2A antagonists Istradafilline X AKINETON (biperiden) [prescribing information]. North Chicago, IL. ebbVie, Inc., 2006; Amantadine [prescribing information]. Minneapolis, MN: Upsher-Smith Laboratories Inc., 2011; APOKYN® [package insert]. Brisbane, CA: Ipsen Group, 2010; Azilect® [prescribing information]. North Wales, PA; TEVA Pharmaceuticals USA, Inc., 2012; Benztropine [prescribing information]. North Wales, PA; TEVA Pharmaceuticals USA, Inc.,2010; COMTAN® (entacapone) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2011; Mirapex® and Mirapex® ER [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc., 2013; Requip® and REQUIP XL™ [package insert]. Research Triangle Park, NC: Glaxo-SmithKline, 2012; Rotigotine (Neupro®) Transdermal System [prescribing information]. Smyrna, GA: UCB,Inc., 2013; Selegiline [prescribing information]. Weston, FL: Apotex Corp, 2003; Sinemet® (carbidopa-levodopa) [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc., 2011; Tasmar® [product insert]. Aliso Viejo, CA: Valeant Pharmaceuticals North America, 2009;. Trihexyphenidyl [prescribing information]. Buffalo Grove, IL. Pack Pharmaceuticals, LLC., 2010. Efficacy of Approved Adjunctive Tx Options for motor fluctuations in PD

Drug class Drug Studies Mean Outcome Average duration time OFF Reduction of Reduction *Adjusted for (hours ) OFF* (hours) by class placebo Dopamine Pramipexole 6 mon 6 -2 1-2h agonists Pramipexole 18 wks -4.5% ER 33 weeks Ropinirole 6 mon 6.9 -0.6 Ropinirole XL 6 mon 7 -1.7 Rotigotine 6 mon 6.5 -0.9 TD Apomorphine *rescue TX SQ MAO-B Selegiline Up to 1h inhibitors Rasagiline 26 weeks 6 -0.5 for0.5mg -1 for 1mg Safinamide 6 mon 5.3 -0.55 COMT- Entacopone 6 mon 5.4 -1.3 Up to 1h inhibitors 6.7 -0.9 Tolcapone 12 weeks 6.2 -0.8-1.8 6.3 -0.9-1.3 Opicapone 15 weeks > 1.5 -.5-1 hour

COMT=catechol-O-methyltransferase; ER/XL=extended release; MAO-B=monoamine oxidase type B

Sinemet® (carbidopa. -levodopa) [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc., 2011. Requip® and REQUIP XL™ [package insert]. Research Triangle Park, NC: Glaxo-SmithKline, 2012. Azilect® [prescribing information]. North Wales, PA; TEVA Pharmaceuticals USA, Inc., 2012. Rotigotine (Neupro®) Transdermal System [prescribing information]. Smyrna, GA: UCB, Inc., 2013 Selegiline [prescribing information]. Weston, FL: Apotex Corp, 2003. COMTAN® (entacapone) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2011. APOKYN® [package insert]. Brisbane, CA: Ipsen Group, 2010. Tasmar® [product insert]. Aliso Viejo, CA: Valeant Pharmaceuticals North America, 2009. Mirapex® and Mirapex® ER [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc., 2013. Amantadine [prescribing information]. Minneapolis, MN: Upsher-Smith Laboratories Inc., 2011. Management of motor fluctuations

Adjunctive Tx Levodopa optimization

 Dopamine agonists  Oral  MAO-Bs  Levodopa ER ( Rytary )  COMTs  Adjustment of dose frequency  A2A antagonists  Adjustment of dose timing  Adjustment of drug/food interaction  Continuous delivery  Duopa – approved  SQ deliveries – in development LEVODOPA 50 years later

Advantages Disadvantages

 Therapeutic gold  Long term motor standard complications  Most potent Dyskinesias antiparkinson drug Motor fluctuations  Fast onset of action Dose failures Lack of disease modifying benefit Hametner E et al. J Neurol. 2010;257(Suppl 2):S268-S275 Schapira AHV et al. Eur J Neurology. 2009;16:982-989 Sinemet® US Prescribing Information. Merck & Co., Inc. Revised 2014/07 Dopamine agonists

Advantages Disadvantages

 Longer half life  Less potent  Less risk of  Higher risk of immediate fluctuations and AEs dyskinesia Somnolence ICD behaviors Orthostatic hypotension

Hametner E et al. J Neurol. 2010;257(Suppl 2):S268-S275 Schapira AHV et al. Eur J Neurology. 2009;16:982-989 Sinemet® US Prescribing Information. Merck & Co., Inc. Revised 2014/07 Other adjunctive Tx (COMT, MAO-Bs, A2A antagonists )

Advantages Disadvantages

 Relatively easy to  Limited potency use (average + 1 hour ON time )

Medical management Surgical management

 Reduction of dopaminergic Tx  STN DBS vs GPi DBS  Amantadine R vs ER (Gocovry) Management of FOG

Types of FOG Management

 Drug responsive  Reduction of OFF time (  Drug resistant – most common drug responsive FOG )  ON freezing – rare  DBS will work only for drug responsive FOG  Physical therapy Management of postural instability and falls

Medical management Surgical management

 No effective TX  STN DBS vs GPi DBS will  Limited data with CEI not work !  Limited data with NE  Limited data with PPN DBS precursor( droxidopa ) though no reproducible results Conclusions

• PD has a wide spectrum of motor manifestations • Accurate diagnosis is essential for prognostication and Tx decisions • There is a wide armamentarium of Tx options for PD motor disability but a n umber of advanced motor manifestations are refractory to TX • Your Tx should be guided by the functional disability establishing clear Tx goals • Tx goals have to be regularly reassessed with the Dx progression

39 Back up slides

• THESE SLIDES SHOULD BE REVIEWED PRIOR TO THE OCTOBER 10 TH L I V E S E S S I O N • PLEASE, TRY TO REVIEW THE KEY PUBLICATIONS THAT ARE REFERENCED IN THESE SLIDES SURGICAL TREATMENT Palliative

FUNCTIONAL SURGERY Indications for surgery  Motor fluctuations /  Pallidal DBS dyskinesia  Subthalamic nucleus DBS*  Medications refractory *most common tremor ( FUS) procedures Contraindications for LESIONING SURGERY surgery  Cognitive impairment !  US guided  Meds refractory thalamotomy symptoms ( but for tremor ) Fox, S et al. 2011, Rascol et al 2015; Kianirad, Simuni, 2016

AAN Practice Parameters Level of Evidence AAN Practice Parameters

AAN Practice Parameters 2002, Reaffirmed 2005. Mov disorders 2018epub

DECIDING Initial Therapy

Patient Considerations Drug Selection • Age • Symptom and Severity • Risk of acute intolerance • Risk of long-term drug-related complications +++ • Comorbidities, especially dementia +++ • Lifestyle, responsibilities • Cost • Compliance • Functional vs. chronological age

Shared Decision-Making

• Physician judgment • Patient-physician relationship

Lyons KE, et al. Int J Neurosci. 2011;121:27-36. Olanow CW, et al. Neurology. 2009;72(suppl 4):S1-S161. Lang AE. Neurology. 2009;72(suppl 2):S39-S43. Efficacy of a novel MAO-B inhibitor as adjunctive TX

Safinamide 016 study Safinamide 016 study

Borgohain R et al, Mov Disord 2014;29(2):229-237 Borgohain R et al, Mov Disord 2014;29(10):1273-1280 Efficacy of a novel COMT inhibitor as adjunctive TX

Opicapone Phase 3 study Opicapone Phase 3 BiPark 2 BiPark1 study

Lees AJ et al, JAMA Neurology 2017;74(2):197-206 Ferreira JJ et al, Lancet Neurology 2016;15(2):154-165 Management of motor fluctuations

Rescue therapies

 Inhaled levodopa  Apomorphine SQ injectable  Apomorphine strip Management of motor disability : across the continuum of the disease

Disease Progression

•MAO-B inhibitor • Levodopa • Levodopa •Dopamine agonist • MAO-B inhibitor • MAO-B inhibitor •Levodopa • Dopamine agonist • Dopamine agonist •Amantadine • COMT inhibitor • COMT inhibitor • A2A antagonist • Apomorphine • Many therapeutic agents may be required over the course of the patient’s disease to maintain patient function • Managing dopamine levels by increasing endogenous levels or supplying exogenous dopamine is critical to successfully treating PD

MAO-B = monoamine oxidase type B; COMT = catechol-O-methyltransferase.

Schapira. Arch Neurol. 2007;64(8):1083-1088., Olanow et al. Neurology. 2009;72(21 suppl 4):S1-S136. , Snyder et al. J Am Acad Nurse Pract. 2007;19:179-197. When should use of an Advanced Therapy be considered?

Increase the frequency of Carbidopa-Levodopa (Sinemet)

Add supplemental medications to prolong the effect of Sinemet and reduce ‘OFF’ time

Optimize the medication regimen

When medicinal options are exhausted and there is still significant ‘OFF’ time, fluctuations, or dyskinesias

Worth, Practical Neurology, 2013 C/L intestinal gel (Duopa®)

Olanow CW et al. Lancet Neurology. 2014;13(2):141-149 Levodopa infusion therapies

 SQ infusion of levodopa/carbidopa

 ClinicalTrials.gov Identifier: NCT01883505  A Phase 2a Study Followed to Evaluate the Safety, Tolerability and Levodopa Pharmacokinetics in Levodopa-treated Parkinson's Disease Patients Receiving ND0612 (ND0612-003)  ClinicalTrials.gov Identifier: NCT02782481  A Clinical Study Investigating the Efficacy, Tolerability, and Safety of Continuous Subcutaneous ND0612 Infusion Given as Adjunct Treatment to Oral Levodopa in Patients With Parkinson's Disease With Motor Fluctuations  Studies on-going  No published data , data preented as abstracts  Data presented in abstract format

Giladi N, et al. ND0612 [abstract 1386]. Mov Disord. 2017; 32 (suppl 2):S546 Olanow CW, et al. ND0612H [abstract LBA41]. Mov Disord. 2016; 32 (suppl 2).