Pramipexole: Hit 3 Birds with 1 Stone China, September 2011 Heinz Reichmann MD, PhD, FRCP Department of Neurology University of Dresden Chairman and Dean

James Parkinson BelladonnaAnticholinergics L-DOPA Transplantation Stem cells ? Amantadine Selegiline COMT-Inhib. Dopamine- Agonists Deep brain stimulationMedic. Neuroprotection ? Neurorestauration ? 200 Years of IPS treatment

When are early patients currently diagnosed? Datamonitor; 2007 Average time in months from onset of symptoms to initial presentation

Could Improved Diagnosis Lead to Different Treatment Regimens? Michell, et al. Brain 2004; 127: 1693 Pathological progression Pre-diagnostic phase Pre-symptomatic Pathological onset Non-specific Specific Symptom onset Treatment Time Diagnosis 1: Diagnosis and treatment expedited if patients present earlier with the characteristic phenotype of disease, and if diagnostic skills are improved : Increasingly plausible to detect the earliest pathological changes (before symptoms develop), potentially allowing the use of neuroprotective agents as early as possible. 2 2: Possible to develop clinical tests that can positively identify earlier symptoms, currently regarded as non-specific.

Moore et al. (2005)

Figure 3: Age-specific risk of PD Risk is estimated with the Kaplan-Meier method for the whole sample and with the maximum-likelihood estimation (ML) for all patients with mutations in LRRK2 combined. Healy et al. (2008)

Schematic diagrams showing the gradual ascent of the pathologic process underlying IPD. b. During the presymptomatic stages 1 and 2, the IPD-related inclusion body pathology is confined to the medulla oblongata and olfactory bulb. c. In stages 3 and 4, the substantia nigra and other nuclear grays of the midbrain and basal forebrain become the focus of initially subtle and, then, severe changes. The illness most probably reaches its symptomatic phase in many individuals. d. In the final stages 5 and 6, the lesions encroach upon the cerebral cortex, so that IPD manifests itself in all of its aspects: somatomotor dysfunctions are supplemented by increasing deterioration of cortically controlled intellectual capabilities. Braak et al Hyposmia – an early symptom

Pre-motor Phase: Symptoms  - Hyposmia, Anosmia, Parosmia - REM-sleep behaviour disorder - Constipation - Depression

Sniffin‘ Sticks

Individual results of testing normal borderline pathological test not performed UPDRS II III TCSSPECT 123 I-FP-CIT (DaTScan) Hummel et al Transcranial sonography in idiopathic olfactory dysfunction UPDRS III Conversion to IPD definitive borderline

Degeneration of sleep related areas may cause sleep disturbances

REM-Sleep Behavior Disorder Dream-associated movements in RBD (lacking atonia)

Follow-up of patients with idiopathic RBD

Gastric  -synuclein inclusions in brain pathology Presence of gastric  -synuclein inclusions could provide first link in susceptible neurons that extend from the enteric to the central nervous system individuals.

Figure 1. Locally administered rotenone induces alpha-synuclein phosphorylation, accumulation and aggregation with gliosis in ENS ganglia. (scale bars 20 mm). A, B, C, anti bIII-tubulin, alpha-synuclein and DAPI staining in duodenum (B) and ileum (A,C) sections. Arrow in B, 1.5 months treatment induced an increased alpha-synuclein punctate pattern inside enteric nervous system ganglia when compared to 3 months controls (A). Arrow in C, 3 months treatment induced formation of larger alpha-synuclein inclusions (|>6 um). D, immunofluorescence staining using anti-alpha-synuclein, Thioflavine S and DAPI. Arrow in D, only 3 month treated mice showed aggregation of these larger alpha-synuclein accumulations. E, F, quantification of the experiment shown in A–C was made using automatic segmentation and entropy-based thresholding methods. Single-asterisk, P<0.05, and double-asterisk, P<0.01. E, each column represents total alpha- synuclein surface/ganglion surface. Pan-Montojo et al. (2010) Duod. Ileum Control

PD: Infectious Disease?

Which patient should be treated? Watch maker Bricklayer

When should we begin treatment for Parkinson’s disease? Early disease – need for symptomatic treatment – symptoms interfere with life, work, etc Early disease – no need for symptomatic treatment Diagnosis Treatment?

Early period – critical time of disease progression Clinical and imaging data both indicate that the early period after diagnosis is critical in terms of the rate of progression a time of opportunity for disease-modifying interventions? StudyDrug UPDRS /year DATATOPSelegiline 12 ROADSLazabemide 8 QE2CoQ10 9 TEMPORasagiline 8.2 ELLDOPAL-DOPA 10.6 TCH

Treatment-naïve PD patients have significantly worse QoL than those receiving treatment Monotherapy with any anti-PD drug Grosset. et al JNNP 2007; 78 (5): 465 Treatment-naïve patients Deterioration Baseline918 0 Follow-up period (months) PDQ-39 single index PD-LIFE: multi-centre prospective audit-based study, on-going, N=198

Timing of Treatment Initiation in PD: A Need for Reappraisal? AHV Schapira, J Obeso 2006 Early correction of the basal ganglia funtional abnormalities caused by dopaminergic cell loss and dopamine deficiency is a means to support the intrinsic phyiological compensatory mechanisms DATATOP, Padberg Study, ELLDOPA, TEMPO, ADAGIO Studies

Diagnosis Decision to treat Decision to refer to neurologist Yes Evaluate patient characteristics and degree of disability Mild motor disability and no cognitive impairment Moderate/Severe motor disability and no cognitive impairment F Moderate/severe disability and age 70–75+ years or with significant co- morbidity including cognitive impairment F Moderate/severe disability and age 70–75+ years or with significant co- morbidity including cognitive impairment Begin dopamine agonist or MAO-B inhibitor Begin dopamine agonist Begin levodopa* Treatment Options in Early PD Schapira AH. Arch Neurol 2007;64(8):

Problems in Long-term Therapy  Induced by treatment - Motor fluctuations - Dyskinesia - Psychiatric complications  Disease-related - Impaired motor function - Motor symptoms unrelated to the dopaminergic system - Autonomic nervous system impairment

Duration of L-dopa Treatment and Frequency of Dyskinesia

28 Dopamine Agonist Use in PD Dyskinesia Dyskinesia by study’s end in the dopamine agonist and levodopa comparison studies % subjects with dyskinesia Ropinirole StudyPramipexole StudyCabergoline Study Levodopa Dopamine agonist Reprinted from Hubble JP. Neurology 2002;58(4 Suppl 1):S42-50, with permission from Lipppincott, Williams & Wilkins. Dopamine agonist-treated subjects had a significantly lower risk for development of dyskinesia

PPX monotherapy in the early stage – randomized dose-finding study Randomized, double-blind, placebo-controlled 264 patients with early IPD, Hoehn &Yahr I-III, not on Levodopa treatment Pramipexole vs. placebo at doses: 1.5 mg/day, 3 mg/day, 4.5 mg/day, 6 mg/day Duration of treatment: 6 weeks titration, 4 weeks maintenance dose Kieburtz et al JAMA, July 9, 1997;278:

Mean % Motor Improvement Efficacy of PPX monotherapy in the treatment of early IPD Motor improvement * * * * * * * * * * Pramipexole (n=162) Placebo (n=168) *(P<.05) Titration and maintenance dose UPDRS Part II total score Weeks Baseline

Randomized, double-blind, placebo-controlled, parallel group comparison 360 patients with advanced IPD, Hoehn &Yahr II-IV in “on”-phases Duration of treatment: 7 weeks titration, 24 weeks maintenance phase Treatment groups: ●Pramipexole 4.5 mg/day + Levodopa ●Placebo + Levodopa Lieberman et al Neurology 1997;49: Clinical efficacy of pramipexole as add-on in advanced IPD

Reduction of mean "off"-hours per day by 31% Reduction of Levodopa dose by 27% Low number of withdrawals due to side effects* Pramipexole = 11.6%; placebo = 10.1% Significant clinical results * Does not include withdrawals due to worsening of disease

Comparison study pramipexole, bromocriptine, placebo in advanced IPD UPDRS – Motor complications (change from baseline) p < 0,02 p < 0, % -14% -5% -30% -25% -20% -15% -10% -5% 0% Pramipexole n=79 Bromocriptine n=84 Placebo n=83 Guttman et al. 1997, Neurology 49:1060

Parkinson patients n=44, advanced stage, combination with L-Dopa; * p<0.01; ***p< Anti-Tremor effect of pramipexole Reduction Physician Assess- ment Physiciant Assess- ment * *** -24% -43% -37% -39% -36% -45% -50% -40% -30% -20% -10% 0% ADL Severity Item 20 UPDRS resting tremor Item 21 UDPRS postural tremor EMG- tremor- frequency Pogarell et al., 2002

Parkinson Study Group, 2000 Pramipexole versus Levodopa in de novo Parkinson patients A double-blind, randomized, controlled multicenter study (CALM-PD 2-years) Pramipexole - clinical studies

CALM-PD JAMA (2000) 284:

Incidence of dyskinesia p< p<0.001 % Patients with dyskinesias 10% 25% 54% 31% 0% 10% 20% 30% 40% 50% 60% 2 years 4 years Pramipexol Levodopa 2-years-data: Parkinson Study Group, JAMA years-data: Parkinson Study Group, JAMA 2002

Occurrence of Dyskinesia in Early PD: the CALM-PD Study (4 years) Corbin A, et al. Parkinsonism Relat Disord 2007;13 (Suppl 2):S106. Adapted from P.Jenner slide presentation, 2009 Reports of dyskinesia as an adverse event Dyskinesia on questionning Pramipexole monotherapy (n = 44) Patients (%) Pramipexole ± levodopa (n = 151) Levodopa total (n = 150) Percentage of Patients with Motor Complications

The Dopamine-Transporter

Initial treatment with pramipexole vs. levodopa: change in striatal b-CIT uptake (SPECT-analysis) pramipexole levodopa %change in striatal  -CIT uptake -30% -25% -20% -15% -10% -5% 0% Study beginnmonth 22month 34month 46 p=0.004 p=0.009 p=0.01

 -Synuclein-pos. Lewy-Body Lewy-Neurite Idiopathic Parkinson‘s Disease – more than dopaminergic Modified according to JELLINGER, 1999 Impaired Region Neurotransmitter Lewy body Nucl. Amygdalae++ Nucleus Basalis MeynertAcetylcholine++ Substantia nigra pars compactaDopamine Nucleus parabrachialis pigmentosus Dopamine++ Nucleus paranigralisDopamine++ Westphal-Edinger KernAcetylcholine+ Nucleus Tegmenti pedunculopontinus Acetylcholine+ Locus coeruleusNoradrenalin++ +++

The Main Symptoms of Idiopathic Parkinson’s Disease Cardinal Symptoms Tremor Rigidity Akinesia Postural instability Hyposmia Additional Symptoms Anxiety, apathy, anhedonia, fatigue, depression, dementia, disturbances of sleep and the autonomic nervous system, pain

Dementia:40.4 % Depression:37.2 % Psychosis:20.4 % Dementia, Depression and Psychosis in German PD patients (n=1,326) DementiaDepression Psychosis < 65 Years Years > 76 Years Prevalence Riedel O, et al. J Neurol 2008;255:

Antidepressive Therapy Antidepressants: -Selective reuptake inhibitors (SSRI, SNRI) - Selective MAO-inhibitors - Traditional antidepressants (TCA)

Anticholinergic effects – Alternation of cognitive functions Sedation Confusion, delirium – Orthostatic hypotension  Poorly tolerated in cognitively impaired elderly patients – Cardiotoxicity Possible serotonin syndrome if associated with the MAO-B inhibitors – however, very rare in clinical practice Tricyclic Antidepressants in PD: Side Effects Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Lieberman A. Acta Neurol Scand 2006;113:1-8. Richard IH, et al. Neurology 1997;48(4):

46 Efficacy of Selective Serotonin and Noradrenaline Reuptake Inhibitors in Depressed PD Patients Conflicting results with regards to efficacy in patients with PD and depression Possible worsening of motor symptoms with SSRIs (fluoxetine, paroxetine and fluvoxamine) – Considered a rare phenomenon Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.

Dopaminergic Pathways

Rationale for Antidepressive Effects of Dopamine Agonists Reduction of “off” periods Dopamine agonist Antidepressive effect Mesolimbic D 3 receptors Lieberman A. Acta Neurol Scand 2006;113:1-8. Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.

Selectivity for D 3 Dopamine Receptors Pramipexole Bromocriptine Ropinirole Cabergoline Pergolide Ratio of binding affinity (K i -values): the higher the number, the higher the affinity for D 3 vs. D 2 Reprinted from Kvernmo T, et al. Clin Ther 2006;28: Copyright © 2006, with permission from Excerpta Medica, Inc. Brecht HM. Akt Neurol 1998;25:S310-S316.

Lemke MR, Reichmann H, et al. J Neuropsych Clin Neurosci 2005;17: © 2005 American Psychiatric Press, Inc. American Psychiatric Publishing, Inc. T1 = baseline T2 = at the end of a maintenance period of 9 weeks on average SHAPS-D: Snaith-Hamilton Pleasure Scale (German version) Pramipexole Improves Anhedonia in PD Anhedonia (Frequency) 3 6 T1 n = 286 (45.7%) T2 n = 160 (25.5%) SHAPS-D (0–14) (P < 0.001)

Effect of Pramipexole on Depressive Symptoms in Parkinson’s Disease Prospective placebo-controlled study to investigate the efficacy of pramipexole in PD patients with: stable motor function and depressive symptoms Prospective placebo-controlled study to investigate the efficacy of pramipexole in PD patients with: stable motor function and depressive symptoms 12-week active treatment phase: 5-week titration-to-response phase (starting at mg up to maximum of 3.0 mg) 7-week maintenance phase Barone P, et al. Lancet Neurol Epub ahead of print.

Pramipexole Significantly Reduces Depressive Symptoms Compared to Placebo (BDI-I) P = 0.01 Change in BDI Total Score -8,0 -7,0 -6,0 -5,0 -4,0 -3,0 -2,0 -1,0 0, Time (Weeks) Pramipexole (n = 139)Placebo (n = 148) Barone P, et al. Lancet Neurol Epub ahead of print.

Pramipexole Was Superior to Placebo in Reducing PD-Related Depressive Symptoms Geriatric Depression Scale (GDS) Total Score after 12 Weeks -4,0 -3,0 -2,0 -1,0 0, Change in GDS Total Score Time (Weeks) Pramipexole (n = 139)Placebo (n = 148) P = 0.03 Barone P, et al. Lancet Neurol Epub ahead of print.

Low correlation between Beck Depression Inventory (BDI) total score and UPDRS Part III total score (0.088, placebo vs , pramipexole) Pramipexole effect on depressive symptoms (path analysis): Results suggest a direct treatment effect of pramipexole on depressive symptoms Pramipexole Reduces Depressive Symptoms in PD Patients Independently of its Effect on Motor Symptoms Change in UPDRS III Change in BDI Treatment effect direct effect 79.6% of total effect, P = % of total effect Barone P, et al. Lancet Neurol Epub ahead of print.

Neuropharmacological Treatment Key Points of Talk Early diagnosis and early treatment are recommended In biologically young patients MAO-B-inhibtiors and/or dopamine agonists should be used In biologicall old patients levodopa should be preferentially used

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