Early Treatment Options When to start, what with, and why?

September 2014 Early Treatment Options When to start, what with, and why? Dr Doug MacMahon FRCP (Lond. & Edin) dgmacmahon@hotmail.com Disclosure Dr MacMahon has received honoraria, fees for advisory boards, and support for attendance at meetings from the following sources: Teva, Lundbeck, UCB, Glaxo SmithKline, MSD, Otsuka, and Norgine. He is a Trustee and Board Member of Parkinson s UK and Clinical Advisor to Adeptio Pharmaceuticals Ltd. He has no relevant financial interests and no conflict of interests to declare. 1

The Modern Management of Parkinson s Disease A spectrum time MuItidisciplinary Comorbidity Interventions Psychopathy Drug Rx Add in Drug Rx Dyskinesia Surgical Rx Education DIAGNOSIS MAINTENANCE COMPLEX Non-Motor Symptoms PALLIATIVE Bradykinesia Wearing off DNAR etc Rigidity Feeding Nutrition, Tremor Pegs etc Advanced Directives Will REASSESS: diagnosis, treatment and support for patient and carers 4 stage paradigm of PD care: Diagnosis Maintenance Mean duration (yrs) 1.6 +/- 1.5 5.9 +/- 4.8 Key Features Recognition Referral to PD specialist Accurate diagnosis Initiate treatment Acceptance Review diagnosis Monitor symptoms Monitor response to treatment Avoid complications Complex 4.9 +/- 4.4 Motor fluctuations Drug side effects Non motor symptoms Falls Palliative 2.2 +/- 2.2 Reduced efficacy of medication Dementia/Psychosis Withdraw unnecessary meds QOL 2

Stages of Parkinson s Disease 1. Wickrematchi 2009 Early or Delayed Treatment in PD? The Diagnosis is Made, Then what? Watch, and wait, or Early interventions? If so, with what? 3

Diagnosis and management - NICE NICE. Clinical Guidance 35, 2006; 3.1: 15 Diagnosis and management - SIGN Diagnosis of Parkinson s Disease Clinical decision to start drug treatment made in collaboration with patient Specialist diagnosis and management Factors determining initial choice include relative drug efficacy, adverse effects, comorbidity and patient preference Dopamine agonist (non-ergot) Levodopa (with dopadecarboxylase inhibitor) Monoamine oxidase B inhibitor Advancing disease with motor complications (these drugs are often used in combination) Drug choice depends on clinical experience, comorbidity & patient preference. There are no robust clinical triggers for adjunctive therapy Catechol-O-methyl transferase inhibitor (prolongs duration of benefit from levodopa) Monoamine oxidase B inhibitor (enhances extrinsic & intrinsic dopamine in the central nervous system) Dopamine agonist (longer half life and duration of action than levodopa; smoothes motor response) Apomorphine (intermittent subcutaneous injection, which reduces off time but has short duration of action) Grosset DG et al. BMJ, 12 Jan 2010. 4

Clinical data now challenge the rationale for delaying treatment NICE key priority Refer to Expert for accurate diagnosis People with suspected PD should be referred quickly and untreated to a specialist with expertise in the differential diagnosis of this condition. NICE clinical guideline CG035 When to start Rx? Patients not started on Rx have significantly worse quality of life 5

First-line treatments NICE recommendations Levodopa Symptomatic treatment in early PD Low dose as possible Maintain good function and reduce development of motor complications Dopamine agonists Symptomatic treatment in early PD Titrate to clinically efficacious dose If side effects prevent this, switch to another agonist or alternative drug class Non-ergot-derived agonist preferred in most cases Ergot-derived require renal function tests, ESR and chest radiograph prior to treatment initiation and annually thereafter MAO-B inhibitors Symptomatic treatment in early PD NICE. Clinical Guidance 35, 2006; 7.2: 62-6 Drug Rx but with what? It is not possible to identify a universal first choice drug therapy for people with early PD. The choice of drug first prescribed should take into account: clinical and lifestyle characteristics patient preference NICE Guidelines CG035 June 2006 6

First-line treatment options There is no single drug of choice in the initial pharmacotherapy of early PD Initial therapy for early PD First-choice option Symptom control Motor complications Risk of side effects Levodopa ü +++ Dopamine agonists ü ++ MAOB inhibitors ü ++ Other adverse events Anticholinergics û Lack of evidence Lack of evidence Lack of evidence Beta-blockers û Lack of evidence Lack of evidence Lack of evidence Amantadine û Lack of evidence Lack of evidence Lack of evidence NICE. Clinical Guidance 35, 2006; 7.2.1: 60 Neuroprotection???? Neurorestoration = The Holy Grail There is currently NO definite proof of neuroprotection from any available drug treatment Can any therapeutic strategy modify disease progression? 7

Early Drug Therapy in PD Are we maximising its benefits? Monotherapy options When to start, and with what? Levodopa MAOI(B) Dopamine Agonists [Amantidine] [Anticholinergics] Early Polytherapy? Dopamine metabolism in the brain Blood brain barrier COMT 3-OMD Presynaptic terminal from the substantia nigra Synaptic vesicle Dopamine transporter D 2 Postsynaptic terminal in the striatum Tyrosine L-dopa TH DDC Tyrosine L-dopa Dopamine DDC MAO-A D 1 Dopamine MAO-B COMT Glial cell Adapted from Youdim et al. Nature Reviews Neuroscience 2006; 7, 295 8

The place of levodopa 1960-2000 1960 s revolutionised Rx of PD 1970-80 s standard Rx for all patients whatever the dose! 1980 s recognition of motor consequences Increasing interest in other options fractionation of levodopa Add-in agonist/selegiline Monotherapy selegiline/agonist 1990 s -2000 early agonist Add-in Entacapone (tolcapone) = COMTI Monotherapy: Levodopa formulations Combined with a DDI to prevent extra-cerebral degradation Levodopa + benserazide (Madopar ) Levodopa + carbidopa (Sinemet ) Slow release tablets (MadoparCR, SinemetCR ) Madopar dispersible Duodopa 9

Levodopa ELLDOPA study Double-blind, placebo-controlled, parallel group, multicentre trial 361 patients with early PD and no prior symptomatic therapy Randomised to receive levodopa either 150mg/day, 300mg/day, 600mg/day or placebo Dosing schedule of three times a day UPDRS of ALL levodopa patients was lower than those of the placebo group After a 2-week washout period at week 42 Fahn S. J Neurol, 2005; 252(Suppl 4): 37-42 Levodopa ELLDOPA study Total Motor AE (not freezing) 37 28 32 57 Fahn S. J Neurol, 2005; 252(Suppl 4): 37-42 10

In de novo disease, early initiation of effective therapy provides long-term benefits vs no treatment 12 Levodopa Change in Total UDRS Score (units) 10 8 6 4 2 0 2 4 Placebo 150 mg 300 mg 600 mg 6 8 2 6 10 14 18 22 26 30 34 38 42 46 Baseline Withdrawal Week of study drug But, at the expense of dyskinesia - so keep dose down Fahn et al, 2004; PSG, 2004 Monotherapy: levodopa pros and cons Pros Used for over 30 years gold standard Effective at preventing slow movements and stiffness and reducing tremor Cons Efficacy reduction over time Common side effects including Dyskinesia Nausea/vomiting Low blood pressure on standing Sleepiness Hallucinations Vivid dreams Prolonged use may be linked to weight loss No evidence that initial use of modified-release levodopa delays onset of motor complications No Place for Early COMT(I) Addition Bachman CG et al. Eur J Neurol, 2009; 16(8): 895-901 NICE. CG35, 2006; 7.1 Stocchi F et al. Annals Neurol July 2010 11

Poor Response to adequate dose? Maybe 10% ipd fail to respond adequately Why??? Concordance? Diagnosis? Distribution of Parkinson Syndromes (PS) Syndrome % of PS cases Idiopathic PD 85% Neurolep5c- induced 7-9% Vascular ~3% MSA ~2.5% PSP ~1.5% Known toxins Very rare Recurrent head trauma Very rare 1. Hughes AJ et al. Neurology, 2001; 57 (10 supplement): S34-8 12

What about agonists? Bromocriptine * Lisuride * Pergolide * relatively low efficacy; Ergot * high side-effect profile, Ergot * three times daily, Ergot * Cabergoline * once (twice) daily 2 Ergot * Ropinirole (ReQuip ) Synthetic; IR tds - XL= od Pramipexole (Mirapexin ) synthetic, IR tds, - PR = od * Ergot related s/e Raynauds Erythromelalgia Effusions Fibrosis Valvulopathy Apomorphine subcutaneous only Rotigotine (Neupro ) synthetic transdermal patch [RISK of AER to patch] Blood brain barrier LEVODOPA DOPAMINE AGONIST D2 D3 D4 D1 D5 Post-synaptic neurones 13

Pramipexole PROUD study Phase I/II, n = 535, multinational, randomised, double-blind, placebo-controlled, parallel group Newly diagnosed idiopathic PD patients 30-75 years Early pramipexole fails to modify PD compared with delayed treatment Schapira et al. Poster at WFN 2009 Pramipexole PROUD Adverse Events Study Phase I Early pramipexole N 261 274 Proportion with Any AEs n (%) 194 (74.3) 196 (71.5) Severe AEs n (%) 34 (13.0) 23 (8.4) Serious AEs n (%) 17 (6.5) 18 (6.6) Study-drug-related AEs n (%) 113 (43.3) 72 (26.3) AEs leading to discontinuation n (%) Study Phase I + II 30 (11.5) 29 (10.6) N 221 214 Proportion with Any AEs n (%) 160 (81.4) 179 (83.6) Severe AEs n (%) 28 (12.7) 24 (11.2) Serious AEs n (%) 22 (10.0) 17 (7.9) Delayed pramipexole (placebo) Study-drug-related AEs n (%) 102 (46.2) 105 (49.1) AEs leading to discontinuation n (%) 16 (7.2) 17 (7.9 ) Schapira et al. Poster at WFN 2009 14

Risks with Agonists: Adverse effects (%) CALM-PD 1 ROP 056 2 CBS 09 3 Adverse Events PPX L-dopa ROP L-dopa CABG L-dopa n = 151 150 179 89 204 208 Nausea 36.4 36.7 48.6 49.4 37.4# 32.2# Somnolence 32.4 17.3 27.4 9.1 26.5* 8.4* Hallucination 9.3 3.3 17.3 5.6 4.3 4.8 Oedema 14.5@ 4.0 14.0 5.6 16.1 3.4 # Includes vomiting, dyspepsia and gastritis - can be avoided/treated with domperidone * Includes sleep disorders, somnolence, insomnia. @ Late onset 1. Parkinson Study Group. JAMA 2000; 284: 1931-8 2. Rascol O et al. NEJM 2000; 342: 1484-91 3. Rinne UK et al. Drugs 1998; 55 (Suppl 1): 23-30 Risks associated with dopamine agonists Dopamine Agonist Withdrawal Syndrome(DAWS) Acute withdrawal symptoms Similar to those seen in cocaine addicts Severe physical and psychological symptoms Correlate with DA withdrawal (dose-dependent) Cause clinically significant distress or social/occupational dysfunction Affects 1 in 3 patients Recurrence of hyperprolactinemia Affects 1 in 5 patients Rabinak CA et al. Arch Neurol 2010;67:58-63 Dekkers OM et al. J Clin Endocrin and Metabol, 2010; 95(1): 43-51 15

Daily Mail July 31st 2012 Impulse control disorders drug-related (?) LEVODOPA DOPAMINE AGONISTS PATHOLOGICAL GAMBLING ICDs HYPERSEXUALITY COMPULSIVE MEDICATION USE Dopamine DysregulaJon Syndrome PUNDING COMPULSIVE SHOPPING EATING Rescue APOMORPHINE or LEVODOPA 16

ICD Dominion study Study of frequency and correlates of 4 ICD Gambling (MAGS) Buying (MIDI) Sexual behaviour (MIDI) Binge eating (DSM IV) 46 PD centres in USA and Canada 3,090 patients 66% taking a DA 87% on levodopa Weintraub et al. Arch Neurol. 2010;67:589-595. ICD Dominion study: ICD frequencies At least 1 ICD in 13.6% of patients >1 ICD in 36% Single ICD frequency Compulsive buying 5.7% Problematic/pathological gambling 5% Binge eating 4.3% Compulsive sexual behaviour 3.5% Weintraub et al. Arch Neurol. 2010;67:589-595. 17

ICD Dominion study: DA vs no DA Increased risk for all ICD behaviours in patients receiving DA medication Weintraub et al. Arch Neurol. 2010;67:589-595. Monotherapy: Dopamine agonists pros and cons Pros Useful in early stages Can be used in combination with levodopa Lower doses of levodopa may be administered Fewer dyskinesias and ON-OFF fluctuations than levodopa in first 5 years Cons Several side effects: mostly class effects Common side effects includes Nausea/vomiting Low blood pressure on standing Confusion and hallucinations Dyskinesia Oedema Vivid dreams Fatigue Impulse Control Disorders 18

Monotherapy: MAO-B inhibitors formulations Currently two licensed Selegiline (Eldepryl + generics) Fast dissolving tablet (Zelapar ) Rasagline (Azilect ) Blood brain barrier MAO-A HVA DOPAC HVA Prolongs effect of endogenous dopamine MAOB(I) MAO-B Long-lasting effect (irreversible inhibition) D2 D3 D4 Post-synaptic neurones D1 D5 19

Monotherapy: MAO-B inhibitors pros and cons Pros Useful in early treatment Delay the need for levodopa Once daily Can be used in combination with levodopa Lower doses of levodopa can be administered May modify (slow) disease progression (Adagio) Generally well tolerated Cons Common side effects may include Headache Nausea Constipation Dry mouth Sleeping disorders (esp selegiline amphetamine metabolites) Postural hypotension Rasagiline - ADAGIO study Objective: to prospectively examine rasagiline as a disease-modifying therapy in PD Design: 18-month, placebo-controlled, double-blind, multicentre trial using a delayed-start design Main inclusion criteria: early PD patients not using any anti-parkinson s medication Recruitment: 1,176 129 centres, 14 countries Olanow et al. Mov Disord 2008; 23: 2194; Olanow et al. N Engl J Med 2009; 361: 1268 20

Rasagiline - ADAGIO study design Early PD patients not using any anti-pd medication (n=1,176) Randomisation 1:1:1:1 Rasagiline 1 mg/day Rasagiline 1 mg/day Placebo Rasagiline 2 mg/day Rasagiline 2 mg/day Visit -4 0 4 12 24 36 42 4 54 60 66 72 (week) 8 36-week (9-month) 36-week (9-month) double-blind double-blind placebo-controlled active-treatment phase phase NB 2mg is an unlicensed dose (n=288) (n=300) (n=295) (n=293) Adapted from Olanow et al. Mov Disord 2008; 23: 2194; Olanow et al. N Engl J Med 2009; 361: 1268 ADAGIO: treating earlier with rasagiline 1 mg/day provided a benefit* that was not achieved by delaying treatment for 36 weeks * These data are derived from a delayed-start study that contained a licensed dose of 1 mg Azilect and an unlicensed dose (2 mg rasagiline) and did not establish a disease-modifying effect for rasagiline ADAGIO showed that the early-start Azilect 1mg group experience significantly less deterioration between baseline and week 72 than the delayed start Azilect group16 This confirmed the benefit of starting Azilect treatment very soon after diagnosis16 ADAGIO:Attenuation of Disease Progression with Azilect Given Once-daily; PD: Parkinson s disease; UPDRS: unified Parkinson s disease rating scale 21

ADAGIO: treating earlier with rasagiline 1 mg/ day provided a benefit* that was not achieved by delaying treatment for 36 weeks ADAGIO subjects who had continuous Azilect monotherapy for nearly 18 months experienced minimal deterioration from baseline over the whole study 18 9 out of 10 (91%) Azilect-treated patients did not require additional anti-pd treatment in the first 36 weeks after diagnosis, significantly less than those receiving placebo 19 * These data are derived from a delayed-start study that contained a licensed dose of 1 mg Azilect and an unlicensed dose (2 mg rasagiline) and did not establish a disease modifying effect for rasagiline ADAGIO: Attenuation of Disease Progression with Azilect Given Once-daily;UPDRS: unified Parkinson s disease rating scale Rasagiline - ADAGIO conclusions 1 ADAGIO the first prospective delayed-start study in PD that uses a 3-component primary analysis to determine disease-modifying effects Rasagiline 1 mg/day fulfilled all three hierarchical primary efficacy endpoints assessed Results suggest that rasagiline 1 mg/day may alter the course of PD Effect was not demonstrated for the 2 mg/day dose* *2mg is an unlicensed dose Olanow et al. N Engl J Med 2009; 361: 1268 22

Rasagiline - ADAGIO conclusions 2 Secondary efficacy endpoints demonstrated that rasagiline was superior to placebo with respect to improvement in UPDRS-Total scores The symptomatic effect observed in the TEMPO study was replicated in the ADAGIO study Rasagiline was well tolerated with few discontinuations due to AEs Olanow et al. N Engl J Med 2009; 361: 1268; Parkinson Study Group. Arch Neurol 2004; 61: 561 Tolerance of Rasagiline in Early treatment The ADAGIO study showed that Azilect was associated with a frequency of adverse events similar to that observed in the placebo group 16 Azilect s long-term tolerability profile was demonstrated for up to 6.5 years in the TEMPO extension study 25 N.B. The FDA did not approve an indication that rasagiline showed evidence of disease modification ADAGIO: Attenuation of Disease Progression with Azilect Given Once-daily; TEMPO: Rasagiline Mesylate [TVP-I012] in Early Monotherapy for Parkinson s Disease Outpatients Neurology Today 03 November 2011; Volume 11(21); pp 1,6-7 23

Burden of disease Health and social care cost implica5ons Annual cost of ~ 2,298 per person (1998 figures) Significant cost drivers include Onset of motor fluctua5ons Frequent cause of falls, fractures and even death Onset of psychiatric symptoms Ins5tu5onal care MacMahon DG et al. Mov Disord, 2000; 15 (suppl 3): 861 NICE. Clinical Guidance 35, 2006; 3.1: 15 Jarman B et al. BMJ, 2002; 324: 1072-5 Thomas S et al. Parkinson s disease society, 1999. Wood BH et al. Journal of Neurology, Neurosurgery & Psychiatry. 2002; 72:721 725. ADAGIO Encore! Rascol O et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011 May;10(5):415-23. Epub 2011 Apr 7. The need for additional antiparkinsonian therapy was reduced with rasagiline 1 mg (25 of 288 [9%] patients) and 2 mg (26 of 293 [9%]) versus placebo (108 of 593 [18%]; odds ratio for 1 mg rasagiline vs placebo 0 41, 95% CI 0 25-0 65, p=0 0002; 2 mg rasagiline vs placebo 0 41, 0 26-0 64, p=0 0001). At week 36, both doses significantly improved UPDRS motor subscores compared with placebo (1 mg rasagiline mean difference -1 88 [SE 0 35]; 2 mg rasagiline -2 18[0 35]; both p<0 0001) and activities of daily living subscores (ADL; 1 mg rasagiline -0 86 [0 18]; 2 mg rasagiline -0 88 [0 18]; both p<0 0001), and 1 mg rasagiline significantly improved UPDRS mentation subscore (-0 22 [0 08]; p=0 004). At week 72, the only significant difference between early-start and delayed-start groups was for ADL subscore with the 1 mg dose (-0 62 [0 29]; p=0 035). When assessed for the effect on non-motor symptoms at week 36, both doses showed benefits on the Parkinson fatigue scale versus placebo (1 mg rasagiline mean difference -0 14 [SE 0 05], p=0 0032; 2 mg rasagiline -0 19[0 05], p<0 0001), and the 1 mg dose showed benefits on the scale for non-motor experiences of daily living compared with placebo (mean difference -0 33 [0 17]; p=0 049). The rate of progression of total UPDRS score for patients in the placebo group was 4 3 points [SE 0 3] over 36 weeks, with extrapolation to about 6 units per year. In the placebo group, patients with the lowest quartile of baseline UPDRS scores ( 14; n=160) progressed more slowly than did those with highest scores (>25 5; n=145; mean difference -3 46 [SE 0 77]; p<0 0001). The rate of UPDRS deterioration was less than was anticipated from previous studies and correlated with baseline severity. INTERPRETATION: These findings show that rasagiline delayed the need for symptomatic antiparkinsonian drugs and emphasise the contribution of the UPDRS ADL in the response of the rasagiline 1 mg per day early-start versus delayed-start group. 24

The place of levodopa 2000-2010 Lower Doses Recogni5on of Agonist limita5ons (ICDs) Availability of Combina5ons in [Later] TCE=Stalevo Rasagiline (Azilect ) Tolcapone (Tasmar ) re- released Now: What to start? What next? PD MED 2 Posters Parkinson s Disease and Related Disorders Shanghai, China. December 11-14 2011 (and verbal presentations by CEC earlier in 2012) NB: As of date of preparation (31 May 2013) These are provisional conclusions Not yet Peer Reviewed or published Work in progress 25

PDMED(Early) A Large, Pragma5c Trial! 1620 pa5ents 2:1 Levodopa sparing (DA or MAOIB):Levodopa Primary Outcome: Mobility dimension on PDQ- 39 2ry outcomes: other dimensions on PDQ- 39 survival etc. PDMED(Early) More Motor Complications on l-d (57% vs 45% @ 5 years) So, conclusions: 1. LD > than LDSparing ( DA, MAOIb or COMTI) 2. MAOIb > DA Analysed on Initial Treatment Choice but, Open; Randomised, but not Double-blind Many changed treatments -?analysis valid Differences very small? Clinical vs statistical significance 26

MAOI(B) Inadequate Control/Wearing Off? PERSON with PARKINSON S DISEASE NEEDING DRUG TREATMENT AGONIST Inadequate Control/Wearing Off? LEVODOPA + DDI Aman*dine, An*cholinergics, B- blockers Max dose? AGONIST or LEVODOPA + DDI MAOI(B)? or LEVODOPA Inadequate Control/Wearing Off? LEVODOPA + DDI ENTACAPONE Inadequate Control/Wearing Off? ENTACAPONE or? AGONIST MAOI(B) ENTACAPONE MAOI(B) Dyskinesia Inadequate Control/Wearing Off? AMANTIDINE and/or Reduce Dose APOMORPHINE (intermi]ent) TOLCAPONE Inadequate Control/Severe Dyskinesia? APOMORPHINE (pump) DUODOPA DBS Drug Rx but with what? It is not possible to identify a universal first choice drug therapy for people with early PD. The choice of drug first prescribed should take into account: clinical and lifestyle characteristics patient preference NICE Guidelines CG035 June 2006 27

THE END Thank you for your attention dgmacmahon@hotmail.com 28