Summary Presentation

Pramipexole (Sifrol Mirapex)

Parkinsons Disease

Boehringer Ingelheim GmbH

Issues: Medical Management of PD

Early Disease
* Establish symptomatic control
* Avoid motor complications
* Modify progression
Advanced Disease

*Maintain symptomatic control

*Control motor-complications
*Control non-motor complications

Dyskinesias and motor fluctuations in

a community-based study of PD
(Schrag et al, 2000)

RESULTS
* Dyskinesias in 28 % of the patients
* Motor fluctuations in 40 % of the patients
* Predictors for the evolution of motor fluctuations:
- Disease duration
- LD dose
* Predictors for the evolution of dyskinesias:
- Duration of treatment

Levodopa-induced
Dyskinesias in Early Onset PD
Duration of LD

% of pts. with dyskinesias

Quinn et al, 1987. (N=40) Schrag et al, 1998.

(N = 99)

6 mths
2 years
5 years
6 years
> 10 years
%

41 %
63 %
94 %
100 %
.

.
.
91 %
.
100

Shortcomings of L-DOPA
Pharmacological
- pro-drug
- absorption and transport failure
- short half-life
- oxidative metabolism (?)
Clinical
- short duration of action
- motor complications
- no effect on progression

Advantages of Dopamine agonists in the

treatment of PD
*
*
*
*

Direct DA-receptor-stimulation
D1-/D2-subspecificity
No transport competition (GI-tract, BBB)
Longer half-life than levodopa (Ropinirole,
Pramipexole, Pergolide, Cabergoline)
* No oxidative metabolism
* Neuroprotection in vitro
- radical scavenging
- antioxidative action
- antiapoptotic action

Patients with motor complications (%)

Pramipexole* Is Associated With a Lower Risk

of Developing Motor Complications
Compared With Levodopa
(2 Years Results)
60
60

Levodopa
Pramipexole

50

P <.001

40
30
20
10
0
0

200

400

600

800

Days From Randomisation

*All pramipexole-treated patients, including those with levodopa supplementation.
Parkinson Study Group. JAMA. 2000;284:1931-1938.

CALM-PD: Pramipexole vs
Levodopa
Incidence of Major Motor Complications at 2 Years
60

%of Patients

50
38%

40
30

30%

24% *

20

10%

10
0
*P = .01.

P = .001.

P = .11.

1%
Wearing Off

Dyskinesia

Pramipexole (n=151)

5%

On-off Effects

Levodopa (n=150)

Levodopa Induces a Higher Incidence of

Dyskinesia Than Dopamine Agonist
Therapy
Patients with dyskinesia

50

Levodopa
Pramipexole
Cabergoline
Ropinirole

40
30
20
10
0

CALM-PD
2 yr

Cabaser 09
5 yr

Requip 056
5 yr

Adapted from Hubble J. Neurology. 2002;58(suppl 1):S42-S50.

Dopamine Agonists vs Levodopa:

Adverse Effect (%)
AEs

CALM-PD1
PRX LD

Requip
0562
ROP LD

Cabaser
093
CAB LD

Pelmopet4
Peg LD

Nausea

36.4 36.7

39 32

37.4 32.2

40 20

Somnolence

32.4 7.3

22 12

26.5 28.4

Hallucinations

9.3

17

4.3

10

3.3

4.8

ROP = ropinirole; CAB = cabergoline; PRX = pramipexole; Peg = pergolide; LD = levodopa.

1.
2.
3.
4.

Parkinson Study Group. JAMA. 2000;284:1931-1938.

Rascol O, et al. N Engl J Med. 2000;342:1484-1491.
Rinne UK, et al. Neurology. 1997;48:363-368.
Oertel WH. Mov Disord. 2000;15(suppl 3):4, Abstract M86.

Dopamine Agonists as initial

monotherapy in PD
- Results from long-term RCTs - Significantly less motor complications compared to
L-Dopa
- About one third remain on agonist monotherapy over
3 - 5 years
- Symptomatic efficacy less than with L-Dopa
(? clinical relevance)
- Increased incidence of hallucinosis compared to levodopa

Evidence-based review of PD therapies

Efficacy of DA-Agonists
* Prevention of disease progression
--> insufficient evidence
* Symptomatic control
--> efficacious: DHEC, Bromocriptine, Cabergoline,
Pergolide, Ropinirole, Pramipexole
--> likely efficacious: Apomorphine, Lisuride
--> insufficient evidence: Piribedil
MDS-Review, Movement Disorders 2002; 17, Suppl. 4

Preclinical rationale and

evidence for the use of DA
in PD
T. Shapira

Potential disease
modifying effects of DA

DA are capable of reducing cell

death in a variety of model systems
in response to a range of toxins
MTPT
rotenone
hydroxydopamine
levodopa
dopamine

Protective properties of
pramipexole
In neuronal cell cultures against a
range of toxins
Neuroprotective action in primate
and rodent models of MPTP
toxicity

Mechanism of action of PPX

mediated neuroprotection not
yet fully understood
PPX is capable of blocking the
pathway to apoptosis
PPX may directly act upon
mitochondrial permeability
Effects of PPX may be
independent of the DA receptor

Imaging data from long-term

studies with dopamine
agonists
Kenneth L. Marek, MD

Outcome Measures for

PD: Neuroprotection
Assessment
Primary CNS Process
Imaging
Compensatory CNS Processes

Functional/Motor Consequences

Motor Ratings
Clinical
Milestones

Neuroimaging Assessment of

PD
Progression
FDOPA
DAT--CIT, CFT,
FDOPA

IPT

6%-11%
reduction/year

Staffen et al, J Neural

Transm, 2000
Nurmi et al, Mov
Disord, 2000
Marek et al,
Neurology, 2001
Pirker et al, Mov
Disord, 2002
Chouker et al, Nucl
Med Commun, 2001

7%-13%
reduction/year

Moorish et al,
Brain, 1996
Nurmi et al, Ann
Neurol, 2001

CALM-PD CIT: Goals

To assess the effect of initial

pramipexole or carbidopa levodopa
treatment on percentage change
from baseline in striatal [123I]-CIT
uptake, a marker of dopamine
transporter density, in a cohort of
early PD patients during a 4-year
period

CALM-PD CIT: Rationale

Dopamine transporter imaging with
[123I]-CIT/SPECT is a biomarker for
PD onset, severity, and progression
In vitro and animal studies suggest
that pramipexole may protect and
that levodopa may either protect or
damage dopamine neurons

Study Design
Screen
CALMCIT

Baseline
Scan
82

Week 10
Scan
13

CALMPD
Study Drug

Month 22
Scan

Month 34
Scan

Month 46
Scan

78

71

65

Percentage Change in Striatal -CIT

Uptake from Baseline by Treatment

% Change from Baseline

10

Pramipexole
Levodopa

0
(39)

(35)
(33)

10
(39)

20

(36)
30

(32)
0

10

20
30
Scan Interval (mo)

40

50

Correlation of Percentage
Change in Striatal CIT Uptake
and Change
in Off UPDRS

Striatum

22 mo
(n = 78)
r = 0.01
P = .94

34 mo
(n = 71)
r = 0.30
P = .01

46 mo
(n = 65)
r = 0.40
P = .001

Conclusions

Patients initially treated with

pramipexole demonstrated a reduction
in the percentage loss from baseline of
striatal [123I]-CIT uptake, a marker of
dopamine neuron degeneration, of
approximately 40% compared with
those initially treated with levodopa
during a 46-month evaluation period

CALM - PD
Pramipexole versus Levodopa in
Early Parkinsons Disease: A 4-Year
Randomized Controlled Trial
Conceived and Conducted by the
Parkinson Study Group
University of Rochester
Rochester, New York

Objectives
To compare initial treatment with pramipexole vs
levodopa in early Parkinsons disease (PD) with
respect to:
The development of:

Dopaminergic complications
Other adverse events, and

Changes in:

Unified Parkinsons Disease Rating Scale (UPDRS)

Quality of life (QOL)

Study Design
Total Follow-up Time: 4 yrs to 4 yrs-10 mo
Feb. 00

Oct. 96

Escalation Phase

Follow-up Period 1

Aug. 01

Follow-up Period 2

Outcome Variables

Time to first motor complication:

Dyskinesias, wearing-off, or on-off
Severity of dyskinesias

Adverse events
UPDRS

Part I (mental), Part II (ADL), Part III (motor)

Quality of life
EuroQol
PDQUALIF

Treatment Effects on Dopaminergic

Endpoints
Pramipexole
(n=151)
%

Endpoints
Value
First Dopaminergic Compl
<.0001
(dyskinesia, wearing-off, on-off)

Levodopa
(n=150)
%

P-

52

74

24

54

47

63

.02

.34

37

25

.01

Individual Complications
Dyskinesias
<.0001
Wearing Off
On-Off effects
Freezing

Dyskinesia, Wearing Off,

or On-Off Effects

74%

52%

Dyskinesia Disability, %
None
Mild
Moderate

Prami
95.6
4.4
0.0

Levo
93.1
5.9
1.0

54%

24%

Reasons for Termination

Pramipexole

Somnolence
11
Edema
6
Dyskinesias
0
Worsened PD Symptoms
8
Nausea/Vomiting
4
Mental Issues
(hallucinations, confusion, other) 4
Lost Interest
Lost to Follow-up
Other Symptoms & Comorbidities
Did Not Consent to Extension

10
1
16
8
68

Levodopa

1
0
3
8
6
4
8
1
12
7
50

Conclusions
Initial

pramipexole reduced the 4year risk of developing the first

dopaminergic event (p < .0001),
dyskinesias (p < .0001) and
wearing off (p = .02).

Conclusions
Initial

levodopa associated with

greater improvement in total
(p = .008), motor (p = .01), and
ADL (p = .03) subscales of the
UPDRS.

Conclusions
Initial

pramipexole associated with

more somnolence, edema, and
cellulitis.

Comparable

effects of initial
pramipexole or levodopa on quality
of life scores.

Should I start my PD patients on

levodopa or pramipexole?
Pramipexole or Levodopa treatment
options
Levodopa

Superior symptomatic UPDRS benefit

Less somnolence and edema

Pramipexole
Reduced dopaminergic motor complications
Slower decline in dopamine transporter loss
as measured by -CIT SPECT uptake