Pramipexole: Hit 3 Birds with 1 Stone

China, September 2011

Heinz Reichmann MD, PhD, FRCP

Department of Neurology

University of Dresden

Chairman and Dean

19001800 20001850 1950

1817James Parkinson

Belladonna

Anticholinergics

L-DOPA

Transplantation

Stem cells?

AmantadineSelegilineCOMT-Inhib.Dopamine-Agonists

Deep brain stimulation

Medic. 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

Pat

hol

ogic

al p

rogr

essi

on

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.

1

3

3: 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 PDRisk 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. 2002.

. .

..

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

TCS SPECT123I-FP-CIT (DaTScan)

Hummel et al. 2006

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. IleumControl

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?

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?

Study DrugUPDRS /year

DATATOP Selegiline 12

ROADS Lazabemide 8

QE2 CoQ10 9

TEMPO Rasagiline 8.2

ELLDOPA L-DOPA 10.6

TCH346 TCH346 7.6

Treatment-naïve PD patients have significantly worse QoL than those receiving treatment

Monotherapy withany anti-PD drug

Grosset. et al JNNP 2007; 78 (5): 465

Treatment-naïvepatients

Det

erio

rati

on

Baseline 9 180

Follow-up period (months)

10

20

30

40

50

60

PD

Q-3

9 si

ngl

e in

dex

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

DiagnosisDiagnosis

Decision to treatDecision to treat

Decision to referto neurologist

Decision to referto neurologist

YesYes

Evaluate patient characteristics and degree of disability

Evaluate patient characteristics and degree of disability

Mild motor disability and no cognitive impairment

Mild motor disability and no cognitive impairment

Moderate/Severe motor disability and no cognitive

impairment

Moderate/Severe motor disability and no cognitive

impairment

FModerate/severe disability

and age 70–75+ yearsor with significant co-

morbidity including cognitive impairment

FModerate/severe disability

and age 70–75+ yearsor with significant co-

morbidity including cognitive impairment

Begin dopamine agonist or MAO-B inhibitor

Begin dopamine agonist or MAO-B inhibitor Begin dopamine agonistBegin dopamine agonist Begin levodopa* Begin levodopa*

Treatment Options in Early PD

Schapira AH. Arch Neurol 2007;64(8):1083-8.

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

2828

Dopamine Agonist Use in PDDyskinesia

Dyskinesia by study’s end in the dopamine agonist and levodopa comparison studies

% s

ubje

cts

with

dys

kine

sia

05

101520253035404550

Ropinirole Study Pramipexole Study Cabergoline 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

studyRandomized, 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;278:125-130

Mea

n %

Mot

or I

mpr

ovem

ent

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

-10

0

5

15

25

35

1 7 11 15 19 23 31

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;49:162-168.

Clinical efficacy of pramipexole as add-on in advanced IPD

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 < 0,0002-27%

-14%

-5%

-30%

-25%

-20%

-15%

-10%

-5%

0%

Pramipexolen=79

Bromocriptinen=84

Placebon=83

Guttman et al. 1997, Neurology 49:1060

Parkinson patients n=44, advanced stage, combination with L-Dopa; * p<0.01; ***p<0.0001

Anti-Tremor effect of pramipexoleR

educ

tion

PhysicianAssess-

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-PDJAMA (2000) 284:1931-1938

Incidence of dyskinesia

p<0.0001

p<0.001

% P

atie

nts

wit

h dy

skin

esia

s

10%

25%

54%

31%

0%

10%

20%

30%

40%

50%

60%

2 years 4 years

PramipexolLevodopa

2-years-data: Parkinson Study Group, JAMA 2000 4-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

0

10

20

30

40

50

60Pramipexole monotherapy (n = 44)

Patie

nts

(%)

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

%ch

ange

in s

tria

tal

-

CIT

upt

ake

-30%

-25%

-20%

-15%

-10%

-5%

0%

Study beginn month 22 month 34 month 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 Meynert Acetylcholine ++

Substantia nigra pars compacta Dopamine ++ +++

Nucleus parabrachialis pigmentosus Dopamine ++

Nucleus paranigralis Dopamine ++

Westphal-Edinger Kern Acetylcholine +

Nucleus Tegmenti pedunculopontinus

Acetylcholine +

Locus coeruleus Noradrenalin ++ +++

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)

10.4

44.5

17.0 18.6

37.3 34.9

67.4

33.7 32.0

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

Dementia Depression Psychosis

< 65 Years

66-75 Years

> 76 Years

Prevalence

Riedel O, et al. J Neurol 2008;255:255-64.

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):1070-7.

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 D3 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 D3 Dopamine Receptors

Pramipexole

Bromocriptine

Ropinirole

Cabergoline

Pergolide

0.4

1.3

7.8

0.5

0.4

Ratio of binding affinity (Ki-values): the higher the number, the higher the affinity for D3 vs. D2

Reprinted from Kvernmo T, et al. Clin Ther 2006;28:1065-78. 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;17:214-20. © 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

T1n = 286 (45.7%)

T2n = 160(25.5%)

SHA

PS-

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

12-week active treatment phase:• 5-week titration-to-response phase

(starting at 0.375 mg up to maximum of 3.0 mg) • 7-week maintenance phase

Barone P, et al. Lancet Neurol 2010. Epub ahead of print.

Pramipexole Significantly Reduces Depressive Symptoms Compared to Placebo (BDI-I)

P = 0.01

Cha

nge

in B

DI

Tot

al S

core

-8,0

-7,0

-6,0

-5,0

-4,0

-3,0

-2,0

-1,0

0,0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Time (Weeks)

Pramipexole (n = 139) Placebo (n = 148)

Barone P, et al. Lancet Neurol 2010. 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

0,0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Cha

nge

in G

DS

Tot

al S

core

Time (Weeks)

Pramipexole (n = 139) Placebo (n = 148)

P = 0.03

Barone P, et al. Lancet Neurol 2010. Epub ahead of print.

• Low correlation between Beck Depression Inventory (BDI) total score and UPDRS Part III total score (0.088, placebo vs. 0.215, 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 = 0.0433

20.4% of total effect

Barone P, et al. Lancet Neurol 2010. 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

Thank you for your kind attention

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