Transcript DUODOPA

DUODOPA®
Feb.05
1
DUODOPA® product and system
Feb.05
2
Parkinson’s Disease
Feb.05
3
DUODOPA®
• An innovative treatment
– A NEW and UNIQUE mode of therapy
– For a limited group of patients suffering from
Advanced Parkinson’s Disease
• Orphan condition
– DUODOPA® is indicated for ADVANCED levodoparesponsive Parkinson’s Disease patients with severe
motor fluctuations and dyskinesias
– A rare clinical profile
► DUODOPA® is an Orphan Drug
Feb.05
4
Advanced Parkinson’s Disease
is an ORPHAN condition
The Orphan condition must affect less than
5 in 10 000 (0,05%) persons in the community
< 230 000 persons in Europe
Epidemiology
PD prevalence :
0.1 % to 0.2 %
European
Population
(25 EU states)
Parkinson’s Disease
Population
690 000
10 % of
prevalence
Advanced PD
with Severe Motor
Fluctuations
69 000 patients
460 000 000
Ref : F.Stocchhi & al Strategies for treating patienst with advanced PD with disastrous
Fluctuations an Dyskinesias.Cl. Neuropharmacology. 1997 Vol.20, N°2, pp.95-115
Feb.05
5
Advanced PD Patients
• Patients significantly limited in their activities despite
treatment with available anti-Parkinson drugs
• Motor complications such as “wearing-off” effect, “on-off”
phenomena, and dyskinesias
• Stage 3 or 4 (Hoehn & Yahr rating scale)
– advanced stage, severely disabling disease
– both sides of the body affected, patients still able to walk and
stand alone but unable to complete day-to-day tasks
– usually cannot live on their own and require substantial help
Ref : MM.Hoehn,MD,and Melvin D.Yahr, MD Parkinsonism : onset, progression, and mortality
Neurology/Vol17/May 1967 : 427-442
Feb.05
6
Progression of Parkinson’s Disease
Response to treatment with Levodopa
• Levodopa : the most effective agent for symptomatic
treatment of Parkinson’s Disease
► still considered the “gold standard” of therapy
• Long term administration of oral Levodopa
► development of motor complications :
“on-off” phenomena – dyskinesia
► limits patients’ ability to fully benefit from levodopa
Feb.05
7
Progression of Parkinson’s Disease
Response to treatment with Levodopa
Freedom from symptoms
ADVANCED PARKINSON
STAGE
Response to treatment
Dyskinesia
”The good years”
Increased
symptom
variation
“On-off”
Disease progression
~ 0-4
Feb.05
~ 4-7
~7-10
~ >10
Years
8
Locus Niger
Feb.05
9
How do motor complications occur?
• Related to the progression of the disease
► continuous death of dopaminergic neurons
► reduced dopamine storage capacity
• With time, after a certain threshold of degeneration the
therapeutic window of levodopa plasma concentration
becomes increasingly narrow
Feb.05
10
Progression of Parkinsons disease
Therapeutic
Window
~ 0-4
Early phase
”the good years”
Ability to store
dopamine
Threshold for
morning dose only
= Normal mobility
= Parkinsonism
Feb.05
~ 4-7
Wearing-off
Short off-periods
~ 7-10
Wearing-off with
dyskinesias
Predictable
fluctuations with
peak-dose
dyskinesias
~ >10
Time (years)
On-off fluctuations
Unpredictable
fluctuations
Very narrow
therapeutic window
Defined therapeutic
window
= Dyskinesia
2
11
Intermittent
Dopaminergic Stimulation
Levodopa uptake is in the upper part of the small intestine
dopamine depletion
+
short half-life of levodopa
+
variable absorption of oral levodopa
due to erratic gastric emptying
Feb.05
►
variability in levodopa
plasma concentrations
below or above the window
▼
“pulsatile”
Dopaminergic Stimulation
12
Continuous
Dopaminergic Stimulation - CDS
By delivering a predictable and constant
infusion of levodopa
▼
Stable levodopa plasma concentrations
▼
Continuous Dopaminergic Stimulation
▼
Reduced motor fluctuations
More continuous benefits for patients
from levodopa therapy
Feb.05
13
DUODOPA®
Reduces both motor fluctuations and dyskinesia
by providing CDS with levodopa
▼
New and effective alternative for
Advanced Parkinson’s Disease patients
Feb.05
14
Galenic formulation issue
Poor solubility of levodopa :
- large infusion volume of levodopa solution
- not possible in practice
► need for special formulation
DUODOPA®
a highly concentrated Intestinal gel
formulation of Levodopa / Carbidopa
H2O
3000 ml
Feb.05
Levodopa 2.000 mg
Carbidopa 500 mg
Gel
100 ml
15
Duodopa® versus Oral Levodopa
Pharmacokinetic profiles
Concentration-time curves. All test days for one patient n°14
Patient 14 Sinemet
plasma levodopa
Baseline
Test day 1
Test day 2
Test day 3
8
7
7
6
6
5
5
4
4
3
3
2
2
1
1
0
D
8
9
10
M
11
D
12
13
Time
Test day 4
Test day 5
Test day 6
8
g/ml
g/ml
Patient 14 Duodopa
plasma levodopa
0
DM
14
15
16
17
M
8
9
10
11
M
12
13
14
15
16
17
Time
Results from clinical study NPP-001-99
Feb.05
16
09
:0
0
08
:0
0
Feb.05
4
3
3
0
4,5
4
3,5
3
2,5
2
1,5
1
0,5
0
4,5
4
3,5
3
2,5
2
1,5
1
0,5
0
17
:0
0
4
17
:0
0
5
16
:0
0
5
16
:0
0
6
15
:0
0
6
15
:0
0
7
14
:0
0
7
14
:0
0
17
:0
0
16
:0
0
15
:0
0
14
:0
0
0,5
13
:0
0
0,5
13
:0
0
1,0
13
:0
0
1,0
12
:0
0
1,5
12
:0
0
1,5
12
:0
0
2,0
11
:0
0
2,0
11
:0
0
2,5
11
:0
0
Sinemet depot
10
:0
0
2,5
10
:0
0
3,0
10
:0
0
3,0
09
:0
0
3,5
09
:0
0
1
08
:0
0
17
:0
0
16
:0
0
15
:0
0
14
:0
0
13
:0
0
12
:0
0
11
:0
0
10
:0
0
09
:0
0
08
:0
0
Patient 7
3,5
09
:0
0
2
08
:0
0
17
:0
0
16
:0
0
15
:0
0
14
:0
0
13
:0
0
12
:0
0
11
:0
0
10
:0
0
09
:0
0
08
:0
0
Patient 14
0,0
08
:0
0
17
:0
0
16
:0
0
15
:0
0
14
:0
0
13
:0
0
12
:0
0
11
:0
0
10
:0
0
Patient 16
Levodopa levels in plasma (2)
Duodopa®
0,0
2
1
0
17
Duodopa® versus Oral Levodopa
Plasma levodopa concentrations - Five Patients cases
Results from clinical study NPP-001-99
Feb.05
18
Clinical development
 Concept test 1991-92 A first test to evaluate the underlying concept of Duodopa®.
 NPP-001-1992 A study of the clinical effect of continuous intraduodenal infusion of a
stabilized suspension of levodopa/carbidopa on patients with on-off phenomena.
 Long-term study-1998 A follow-up on long-term utility of Duodopa treatment.
 NPP-001-1999 A comparison of the plasma levodopa variability during continuous
intraduodenal infusion of a levodopa/carbidopa and oral levodopa/carbidopa in patients
with advanced Parkinson’s disease.
 NPP-002-2000 A retrospective study investigating how long patients treated with
Duodopa® had received their medication.
 NPP-001-2002 (DIREQT) A study of the effect on motor fluctuations and on
Quality of Life aspects.
 NPP-002-2002 An assessment of safety as well as global efficacy and variability in
dose requirements.
Feb.05
19
Publications on Duodopa®
 Bredberg et al. Intraduodenal infusion of a water-based levodopa
dispersion for optimisation of the therapeutic effect in severe Parkinson's
disease. Eur J Clin Pharmacol 1993; 45: 117-122.
 Nilsson et al. Long-term intraduodenal infusion of a water based levodopacarbidopa dispersion in very advanced Parkinson's disease.
Acta Neurol Scand 1998; 97: 175-183.
 Nilsson et al. Duodenal levodopa infusion in Parkinson’s disease – longterm experience. Acta Neurol Scand 2001; 104: 343-348.
 Nyholm et al. Optimizing levodopa pharmacokinetics – intestinal infusion
versus oral sustained-release tablets.Clin Neuropharm. 2003; 26:156-163
 Nyholm et al. Duodenal levodopa infusion monotherapy versus oral
polypharmacy in advanced Parkinson disease. Neurology 2005; 64:216-223
Feb.05
20
Duodopa® benefits and risks
• Efficacy on core symptoms of Parkinson’s Disease similar to levodopa
oral formulation
• Additional benefits due to Continuous Dopaminergic Stimulation :
►
Control of the « ON-OFF » fluctuations
► By maximizing the functional « ON-time » during the day with less
« OFF » episodes
and less « ON-time » with dyskinesia
• Adverse event profile similar to oral Levodopa / Carbidopa
• No unexpected tolerability or safety issues
► Only minor problems due to the Duodopa® delivery system
• No death related to the treatment
Feb.05
21
Duodenal levodopa infusion
monotherapy vs oral polypharmacy in advanced Parkinson’s disease
NEUROLOGY Jan.25th 2005; 64:216-223
• Objective :
– to compare daytime intraduodenal levodopa/carbidopa infusion
as monotherapy with individually optimized conventional
combination therapies in patients with advanced PD for Motor
Fluctuations and QoL
• Methods :
–
–
–
–
Randomized, controlled, multi-center study
24 patients enrolled (6 women & 19 men)
Cross over study design (3weeks + 3weeks)
Video scoring of motor function by blinded assessors on a global
treatment response scale (-3 to 0 to +3)
– Patient self-assessment with electronic diary
Feb.05
22
Duodenal levodopa infusion
monotherapy vs oral polypharmacy in advanced Parkinson’s disease
NEUROLOGY Jan.25th 2005; 64:216-223
• Results with Duodopa®
– Median percentage of ratings in functional «ON» interval
(-1 to +1) increased from 81 to 100% (p<0.01)
– Decrease in «OFF» state and no increase in dyskinesia (p<0.01)
– Median UPDRS score decreased from 53 to 35 in favor of
Duodopa (p<0.05)
– Quality of life improved: PD Questionnaire-39 and 15D Quality of
life Instrument (p<0.01)
– Adverse events similar for both treatments
Feb.05
23
DUODOPA®
in clinical practice
Feb.05
24
®
DUODOPA
• Intestinal Gel
– Concentrated suspension of
levodopa/carbidopa
(2g / 0.5g for 100 ml)
– Same ratio 4:1 as common
oral formulations
– Cassette of 100ml
• Levodopa 20 mg/ml
• Carbidopa 5 mg/ml
– Box with 7 cassettes
• Portable pump
– Specially designed
– Programmable to allow
individualized dose regimen
infusion
– Security features available :
• Specially designed software
• Alarms
• Controlled programming
Feb.05
25
DUODOPA® Treatment
TEST PERIOD
Temporary Nasoduodenal
tube to test the clinical
response
Feb.05
PERMANENT Treatment
Permanent catheter implanted into the
duodenum via a Percutaneous Endoscopic
Gastrostomy (PEG)
26
DUODOPA® TEST PERIOD (1)
• Temporary treatment
► 3 to 5 days duration
• Evaluation of positive
clinical response
• Dose titration
• Fine tuning to individual
needs
• Steps as little as 2 mg of
levodopa
• Pump acceptability
and handling
Feb.05
27
®
DUODOPA
TEST PERIOD (2)
• Adjustable dose Schedule
– Morning bolus dose
• To rapidly reach a steady state of
plasma concentration
– Maintenance infusion rate
• During the day (over 16 hours)
• Exceptionnally during 24 hours
– Extra doses
• As little as 2 mg of levodopa
• Can be self administered by the
patient when needed
Feb.05
28
®
DUODOPA
PERMANENT Treatment
• Continuous intra-intestinal
infusion
– Through a permanent catheter
implanted into the duodenum via a
Percutaneous Endoscopic
Gastrostomy (PEG)
under local anesthesia
• Monotherapy
– For most patients on a long term
treatment
• Individual adaptation of
dose
– Fine tuned titration
– Morning and extra doses and
infusion rate adjustable
in steps of 2 mg
Feb.05
29
ORPHAN EUROPE Services
• Material for Duodopa® system :
–
–
–
–
Nasointestinal tube
PEG tube / Inner tube
Pump delivery and service
Holster, vest or belt….
► provided free of charge by
ORPHAN EUROPE
• Additional services :
– Educational support (patient, family, caregivers… )
– Hospital staff support
Feb.05
30
DUODOPA® Patients
Feb.05
31
DUODOPA® Patient profile
How to select the first patient to build up experience :
- Severe motor fluctuations
- Tried different oral drug combinations
- Clear response to levodopa
► good “ON” period
- Preferably no dementia
- Preferably no depression
- No age limit restrictions
Feb.05
32
DUODOPA® Swedish experience
General profile of the Duodopa® patients
• Number of treated patients : ► ~ 100
• Age :
– 49-82 years old
– most of them were between 55 and 70 years old when they started
• Prior treatment duration with various combinations of PD
therapies before Duodopa®
► 10-15 years
• Average duration with Duodopa® treatment :
► ~ 4 years
Feb.05
33
Case Study – Swedish patient
History of the disease
Born in 1951
Professor of Physics in Uppsala University
First Symptoms of PD in 1991 : 40 years old
In 1999 :Unpredictable motor complications
« ON » periods of good quality with levodopa
Different Treatments
1991-2000 : Oral treatments with levodopa /selegiline/cabergoline
In 2000 : Included in a trial with Duodopa® via nasoduodenal tube.
He was well–controlled but at the end of the study
► Reluctant to a permanent infusion system
► He refused a DBS afraid of risks associated with Neurosurgery
► He came back to previous oral treatments
In 2001 : increasing motor fluctuations
► Levodopa combined with Apomorphine infusion
In 2002 : He is included in a new trial with Duodopa® on Monotherapy
Then he chose the permanent treatment with DUODOPA® since March 2003
Feb.05
34
Case Study – Swedish patient
Follow-up
On monotherapy with DUODOPA® he improved considerably
Patient fully satisfied with his new treatment and very well
equilibrated.
Only minor motor fluctuations observed
He is still under monotherapy during the day (6 am to 10 pm),
he takes oral levodopa during the night but no other medications
He can now work on a 75 % basis.
… and he goes to his work by bike!
Feb.05
35
Conclusion
• Unmet medical need fulfilled :
► Continuous Dopaminergic Stimulation
achievable with Levodopa
as Monotherapy
• Patient’s positive response is confirmed before
permanent treatment (Test period)
• Individualized treatment :
► adjustable in steps of 2 mg (0.1ml)
► efficient
► safe
• Improved Quality of life
Feb.05
36
BACK-UP
Feb.05
37
Case Study – German patient n°1
History of the disease
Born in 1936 - Female
1973-1995 : Symptoms of PD
1995 : Diagnosis of PD (59 years old)
2003 : Severe motor complications
« ON » periods of good quality with levodopa
Different Treatments
1973-1995 : psychopharmaceutical drugs
1995-2004 : oral treatments : combination of Levodopa and dopaminergic agonists
2004
: Heavy fluctuations – switch within 15 min from -3 to +3
Very short normal « ON » phases in a day
DBS and Apomorphin refused by the patient
Nov 2004 : DUODOPA® implementation
Follow up
Increased « ON » periods, with clear clinical improvements
Patient very satisfied : fantastic improvement of her daily live
Feb.05
38
Case Study- German patient n°2
History of the disease
Born in 1941 – Male – Architect
1985 : First symptoms of PD (48 years old)
Since 2003 : Severe motor complications and psychotic symptoms
though oral treatments
Some « ON » periods of good quality with levodopa
Different treatments
1985 - 2004 : Oral treatments : combination of Levodopa, dopaminergic and
agonists COMT inhibitors
DBS refused by the patient
Dec 2004 : DUODOPA® implementation
Follow up
Increased « ON » periods, about 95% compared to previous treatment
Only 2 or 3 short “OFF” periods per day well controlled with extra doses
No psychotic symptoms any more
Patient extremely satisfied
Feb.05
39
DIREQT
Duodopa® Infusion - Randomised
Efficacy and Quality of life Trial
• Duodopa® monotherapy vs any combination of
conventional medication
• 24 patients, 5 centres in Sweden
• Video recordings, ”blinded” scoring
• Efficacy and Quality of Life - electronic home diary
Nyholm et al., 2005
Feb.05
40
DIREQT – Study design
Black boxes = duodenal levodopa/carbidopa gel infusion monotherapy.
White boxes = conventional combination pharmacotherapy.
Arrows pointing downwards indicate video recordings every 30 min. for 8 hrs.
Figures indicate weeks.
Nyholm et al., 2005
Feb.05
41
Treatment response scale
Video Scoring
Percentage of recordings in grouped intervals of
the Treatment Response Scale
-3 to -2 = severe OFF to moderate OFF
-1 to +1 = mild OFF, normal, mild dyskinesia
(”functional ON”)
+2 to +3 = moderate dyskinesia; severe dyskinesia
Feb.05
42
Video Scoring
• Video recording every 30 min from 8 am to 5 pm (18 points) 4 tasks:
–
–
–
–
Piano playing
Alternate hands movement
Getting up from a chair
Walking
• Motor abilities evaluated by investigator on the rating scale
• Rating from video scoring shows that patients treated with
DUODOPA® spent more time in “normal” motor state on infusion
and less time in both “OFF”state and “hyperkinetic” state
-3
Severe parkinsonism
-2
Parkinsonism
-1, 0, +1 “On”
+2
+3
Feb.05
“OFF” State
“Normal” motor State
Dyskinesia
Severe dyskinesia
“Hyperkinetic” State
43
Dose rating scheme
Tablets
9/5 2002 R-M G
+3
+2
+1
0
-1
-2
-3
06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Morning dose
Speed
Extra dose
Other
treatment
Tablet treatment
Feb.05
44
Dose rating scheme
Duodopa®
15/5 2002 R-M G
+3
+2
+1
0
-1
-2
-3
06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Morning dose
2 ml
40
mg
Speed
34
1.7mg/h
ml/h
12 mg
0.6
ml
Extra dose
16
0.8mg
ml
Other
treatment
Duodopa® : Levodopa 20 mg/ml - Carbidopa 5 mg/ml
Feb.05
45
DUODOPA®
Gel formulation Advantages
Problems with existing
Levodopa formulations
Solved by
DUODOPA® formulation
Limited solubility, large volumes
(1-2 mg/ml =1000 - 2000 ml to
cover a daily need of 2000 mg)
20 mg/ml covers a daily need of
2000 mg in a 100 ml cassette.
Poor stability of solution in room
temperature and light, supply
needs to be changed during the
day
Good long-term stability in
refrigerator, the content of one
cassette is stable for a whole day
at room temperature.
Large infusion pumps
Portable specially designed pump,
weights about 18 oz. (510g)
including a full cassette.
Feb.05
46
DUODOPA® storage condition
• Deep frozen at end of manufacture
► Can be stored for 2 years in freezer at – 20°C
• At the pharmacy storage and patient’s house
► Must be kept refrigerated between 2°C to 8°C
• 15 weeks shelf-life when stored in refrigerator
• The gel suspension in 1 cassette is stable 24 hours at
room temperature
Feb.05
47
Advantages of
Problems with
Oral Levodopa/Carbidopa
®
DUODOPA
Solved by the
DUODOPA® administration
Fluctuating pharmacokinetics due to
erratic gastric emptying, i.e.
“pulsatile” dopaminergic
stimulation
Smooth pharmacokinetics due to
constant infusion to the site of
absorption, i.e. Continuous
Dopaminergic Stimulation
Extra tablet doses of 50-100 mg may
add to the previous dose, due to
delayed gastric emptying, forming
high peak concentration and severe
dyskinesia
Extra doses of e.g. 10 mg,
adjustable in steps of 2 mg, do not
produce any marked peaks in the
concentration curve, i.e. the patient
turns “ON” without dyskinesia
Individualized therapy is difficult with The morning dose and extra doses
tablet strengths of 50-200 mg
are adjustable in steps of 2 mg and
the infusion rate in steps of 2 mg/hr
Feb.05
48