Two-year, placebo-controlled safety and
tolerability data for safinamide as add-on to
L-dopa in patients with Parkinson’s disease
2.266
Rupam Borgohain,1 Jozsef Attila Szasz,2 Paolo Stanzione,3 Rodolfo Giuliani,4 Valentina Lucini,4 Ravi Anand,5 for the Study 018 Investigators
Nizam’s Institute of Medical Sciences, Hyderabad, India; 2Emergency County Hospital, Targu Mures, Romania; 3Clinica Neurologica, Università di Tor Vergata, Rome, Italy;
4
Newron Pharmaceuticals SpA, Bresso, Italy; 5APC AG, St Moritz, Switzerland
1
Presented at the XIX World Congress on Parkinson’s Disease and Related Disorders, Shanghai, China, 11-14 December 2011
Objective
• To evaluate the long-term safety and tolerability of
safinamide as add-on to levodopa (L-dopa) in patients
with Parkinson’s disease (PD) and motor fluctuations.
Background
• Although L-dopa is highly effective for treating PD
motor symptoms, its long-term use is associated with
motor fluctuations and dyskinesia.1
—According to one estimate, ~40% of patients
develop motor complications after 4–6 years of
L-dopa treatment.2
• Patients with L-dopa-induced motor fluctuations usually
require add-on therapy, with the aim to prolong ON time
while reducing, or at least not exacerbating, dyskinesia.
—Agents combining dopaminergic and non-dopaminergic
mechanisms of action may address these needs.
—Currently available add-on dopaminergic therapy may
improve motor functions, but often at the expense
of worsening dyskinesia.
• Safinamide is an ␣-aminoamide in Phase III clinical
development as add-on therapy to L-dopa or dopamine
agonists in patients with PD.
• Safinamide has both dopaminergic and non-dopaminergic
mechanisms of action including3-5:
—Reversible, highly selective inhibition of monoamine
oxidase Type B (MAO-B).
—Activity-dependent sodium-channel antagonism.
—In vitro inhibition of glutamate release.
• Study 018 was a double-blind, placebo-controlled,
parallel-group, 18-month extension to Study 016, which
was a multi-center, international, Phase III trial that
evaluated the long-term efficacy and safety of two doses
of safinamide (50 and 100 mg/day) versus placebo in
PD patients with motor fluctuations despite optimized
L-dopa treatment.6,7
• The current analysis presents an evaluation of the
long-term (2-year) safety and tolerability of safinamide
based on Studies 016 and 018.
• The safety population of Study 016 consisted of all
patients taking at least one dose of study medication
and having at least one post-baseline safety
assessment.
• The safety population of Study 018 consisted of
all patients enrolled in the extension phase since, by
definition, they had at least one dose of study medication
and at least one post-baseline safety assessment.
• Safety and tolerability were assessed based on
incidence of reported treatment-emergent adverse
events (TEAEs) and from laboratory, vital-sign, and
electrocardiographic data.
• Newly-emergent TEAEs were defined for Study 018
as those not reported during the 6-month duration of
Study 016 and those reported in Study 016 that
occurred with greater intensity during the extension.
• All safety/tolerability assessments pertained to the
extension-study safety population, defined as all patients
who received at least one dose of study medication and
underwent at least one post-dose safety assessment
during the extension.
• Neurological, ophthalmological, and dermatological
examinations were carried out, and the Epworth
Sleepiness Scale8 was used to assess daytime
sleepiness.
Results
Table 1. Demographic and clinical characteristics of the
intent-to-treat (ITT) population at baseline.
Placebo
(n=222)
Characteristic
Gender, n (%)
Study design
• Study 018 was a prospective, double-blind, placebocontrolled, parallel-group 18-month extension of Study
016, a pivotal 6-month Phase III study (Figure 1).6,7
Patients
receiving
levodopa
Screening
(10 days)
Levodopa
stabilization
phase
(4 weeks)
Initial Study
Extension Study
Primary endpoint:
ON time with no/minor dyskinesia
Primary endpoint:
Dyskinesia Rating Scale
Placebo
Placebo
Safinamide 50 mg/day
Safinamide 50 mg/day
Safinamide 100 mg/day
Safinamide 100 mg/day
6 months (n=669)
18 months (n=544)
Figure 1. Design of the initial study (Study 016)
and its extension (Study 018).
Patients
• Key inclusion criteria for Study 016 included:
—Male or female, 30−80 years of age
—Idiopathic PD of ≥3 years duration
—Hoehn & Yahr stage I–IV during OFF phase
—Treatment with stable doses of L-dopa
—Experiencing motor fluctuations with >1.5 hours of
OFF time per day
• Key exclusion criteria for Study 016 included:
—Severe, disabling peak-dose or biphasic dyskinesia
—Unpredictable or widely swinging PD symptom
fluctuations
—Evidence of dementia, cognitive dysfunction, or
depression
—MAO inhibitor use
• For inclusion in the 18-month extension, patients were
required to:
—Have 24 weeks of observation in Study 016
—Be adherent to the study medication regimen
—Demonstrate the absence of clinically significant
adverse events (AEs)
—Display a lack of progression to Hoehn & Yahr stage V
Treatments
• Patients continued the double-blind treatment they had
been taking in Study 016:
—Safinamide 100 mg/day
—Safinamide 50 mg/day
—Placebo
• Patients unable to tolerate safinamide 100 mg/day
had their dosage decreased to 50 mg/day.
• Dosage of L-dopa or other ongoing PD therapies could
be changed, and PD medications (excluding MAO
inhibitors) could be added.
Safinamide Safinamide
50 mg/day 100 mg/day
(n=223)
(n=224)
Male
Female
160 (72.1)
62 (27.9)
157 (70.4)
66 (29.6)
163 (72.8)
61 (27.2)
Asian
White
180 (81.1)
42 (18.9)
180 (80.7)
43 (19.3)
179 (79.9)
45 (20.1)
59.4 (9.4)
60.1 (9.7)
60.1 (9.2)
PD duration, years, mean (SD)
8.3 (3.8)
7.9 (4.0)
8.2 (3.8)
H&Y stage, mean (SD)
2.8 (0.7)
2.8 (0.6)
2.8 (0.6)
Race, n (%)
DRS score, mean (SD)
3.4 (3.9)
3.9 (3.9)
3.7 (4.1)
ON time, hrs/day, mean (SD)
9.3 (2.2)
9.4 (2.3)
9.5 (2.4)
OFF time, hrs/day, mean (SD)
5.3 (2.1)
5.2 (2.1)
5.2 (2.2)
UPDRS-II score, mean (SD)
12.3 (5.9)
11.8 (5.7)
12.1 (5.8)
UPDRS-III score during ON,
mean (SD)
28.7 (12.0)
PD-drug use, n (%)
L-dopa
Dopamine agonist
Entacapone
Anticholinergic
Amantadine
222 (100.0) 223 (100.0) 224 (100.0)
137 (61.7) 142 (63.7) 128 (57.1)
56 (25.2)
52 (23.3)
55 (24.6)
87 (39.2)
74 (33.2)
87 (38.8)
34 (15.3)
29 (13.0)
30 (13.4)
27.3 (12.7) 28.3 (13.3)
H&Y, Hoehn & Yahr; PD, Parkinson’s disease; SD, standard deviation;
UPDRS, Unified Parkinson’s Disease Rating Scale; UPDRS-II: Activities of daily living;
UPDRS-III: Motor examination.
• 544 (81.3%) of the patients in Study 016 entered the
018 extension study.
• Among the patients in Study 018, 440 (80.9%)
completed a total of 24 months of treatment including:
—142 (81.1%) of 175 patients in the placebo group
—148 (78.3%) of 189 patients in the safinamide
50 mg/day group
—150 (83.3%) of 180 patients in the safinamide
100 mg/day group
• The safety population of Study 018 consisted
of 175 patients in the placebo group, 189 in the
safinamide 50 mg/day group, and 180 in the safinamide
100 mg/day group.
• Of the patients receiving safinamide 100 mg/day,
5 patients had dose changes:
—Three patients had their dose of safinamide
decreased to 50 mg/day and this decrease was
maintained throughout the study.
—Two patients had their dose decreased for
4–6 weeks followed by an increase in the dose,
which was maintained for the rest of the study.
• The mean change in L-dopa dose was an increase
of 17.7% in the placebo group compared with 9.9%
for safinamide 50 mg/day (p=0.2024) and 5.0% for
safinamide 100 mg/day (p=0.0044).
• There were no statistically significant changes in the
levels of any other PD medications.
Safinamide Safinamide
50 mg/day 100 mg/day
(n=189)
(n=180)
Adverse-event category, n (%)
Placebo
(n=175)
Any TEAE
160 (91.4)
168 (88.9)
163 (90.6)
• Rates and reasons for discontinuation were generally
similar among the treatment groups (Table 5).
Table 5. Adverse events leading to discontinuation of
>1 patient in any group during the 2-year treatment
duration (Study 016 and 018) in the Study 018
safety population.
Incidence, n (%)
Newly emergent TEAEs during
Study 018
149 (85.1)
145 (76.7)
141 (78.3)
Adverse-event type,
MedDRA preferred term
Placebo
(n=175)
Safinamide Safinamide
50 mg/day 100 mg/day
(n=189)
(n=180)
Re-emergent TEAEs during
Study 018
21 (12.0)
18 (9.5)
19 (10.6)
Any serious TEAE
28 (16.0)
32 (16.9)
34 (18.9)
Sepsis
3 (1.7)
1 (0.5)
1 (0.6)
Discontinuation due to TEAEs
10 (5.7)
10 (5.3)
12 (6.7)
Parkinson’s disease
2 (1.1)
1 (0.5)
1 (0.6)
Death*
6 (3.4)
3 (1.6)
5 (2.8)
Sudden death
1 (0.6)
1 (0.5)
2 (1.1)
Dyskinesia
1 (0.6)
2 (1.1)
0 (0.0)
Myocardial infarction
0 (0.0)
0 (0.0)
3 (1.7)
Pyrexia
2 (1.1)
0 (0.0)
0 (0.0)
Discomfort
0 (0.0)
0 (0.0)
2 (1.1)
Cardiac arrest
1 (0.6)
0 (0.0)
1 (0.6)
*based on patient disposition
• TEAEs were generally of mild or moderate severity, and
severity did not appear to be dose-dependent (Figure 2).
100
• The baseline demographic and clinical characteristics of
the ITT population were generally well balanced among
treatment groups (Table 1).
Age, years mean (SD)
Methods
Table 2. Summary of treatment-emergent adverse events
(TEAEs) reported during the 2-year treatment duration
in the Study 018 safety population.
Proportion (%) of Patients
Safety/tolerability parameters
80
13.7%
11.6%
14.4%
Severe
Pneumonia aspiration
1 (0.6)
0 (0.0)
1 (0.6)
34.9%
40.2%
36.1%
Moderate
Respiratory failure
1 (0.6)
0 (0.0)
1 (0.6)
Cardio-respiratory arrest
0 (0.0)
1 (0.5)
1 (0.6)
60
40
• The incidence of serious TEAEs was generally balanced
across treatments (Table 6).
42.9%
40.0%
37.0%
Mild
20
0
Placebo
(n=175)
Safinamide
50 mg/day
(n=189)
Incidence, n (%)
Safinamade
100 mg/day
(n=180)
Figure 2. Severity of treatment-emergent adverse events
during the 2-year treatment duration in the Study 018
safety population.
• During the 18-month extension represented by Study
018, the three most common newly emergent TEAEs
were ongoing PD, dyskinesia, and cataract (Table 3).
Table 3. Most frequent newly emergent and
re-emergent adverse events during Study 018.
Incidence, n (%)
Adverse-event type,
MedDRA preferred term
Newly emergent with an incidence
≥5% in any group
Parkinson’s disease
Dyskinesia
Cataract
Asthenia
Pyrexia
Fall
Back pain
Insomnia
Weight decreased
Constipation
Hypertension
Pain in extremity
Arthralgia
Re-emergent occurring in >1 patient
in any group
Dyskinesia
Back pain
Fall
Dry mouth
Weight decreased
Parkinson’s disease
Abdominal pain
Hyperchlorhydria
Safinamide Safinamide
50 mg/day 100 mg/day
(n=189)
(n=180)
Placebo
(n=175)
29 (16.6)
27 (15.4)
18 (10.3)
13 (7.4)
13 (7.4)
13 (7.4)
9 (5.1)
7 (4.0)
8 (4.6)
8 (4.6)
6 (3.4)
5 (2.9)
5 (2.9)
2 (1.1)
3 (1.7)
2 (1.1)
4 (2.3)
0 (0.0)
3 (1.7)
0 (0.0)
0 (0.0)
32 (16.9)
24 (12.7)
21 (11.1)
10 (5.3)
14 (7.4)
13 (6.9)
9 (4.8)
18 (9.5)
13 (6.9)
12 (6.3)
7 (3.7)
10 (5.3)
10 (5.3)
6 (3.2)
1 (0.5)
1 (0.5)
0 (0.0)
2 (1.1)
0 (0.0)
0 (0.0)
0 (0.0)
38 (21.1)
24 (13.3)
18 (10.0)
16 (8.9)
11 (6.1)
11 (6.1)
14 (7.8)
6 (3.3)
8 (4.4)
9 (5.0)
11 (6.1)
7 (3.9)
7 (3.9)
4 (2.2)
2 (1.1)
3 (1.7)
0 (0.0)
2 (1.1)
0 (0.0)
2 (1.1)
2 (1.1)
• The three most common re-emergent TEAEs were
dyskinesia, back pain, and falls (Table 3).
• During the 2 years of treatment, the incidence of the
most common TEAEs was similar across treatment
groups except for dyskinesia, which was more frequent
in the safinamide groups than in the placebo group
and reflected a slight excess in the first six months
(Table 4).
Table 4. Most frequent treatment-emergent adverse
events occurring in ≥10% of patients in any group during
the 2-year treatment duration (Study 016 and 018) in
the Study 018 safety population.
Incidence, n (%)
Adverse-event type,
MedDRA preferred term
Placebo
(n=175)
Table 6. Most frequent serious treatment-emergent
adverse events occurring in >2 patients in any group
during the 2-year treatment duration (Study 016 and 018)
in the Study 018 safety population.
Safinamide Safinamide
50 mg/day 100 mg/day
(n=189)
(n=180)
Dyskinesia
38 (21.7)
59 (31.2)
50 (27.8)
Parkinson’s disease
24 (24.0)
42 (22.2)
43 (23.9)
Cataract
27 (15.4)
27 (14.3)
25 (13.9)
Safety/tolerability
Back pain
21 (12.0)
17 (9.0)
23 (12.8)
• Overall, the incidence of any TEAE was generally
similar among the treatment groups during the 2 years
of treatment (Table 2).
• Both newly emergent TEAEs and re-emergent TEAEs
had similar incidences across treatment groups (Table 2).
• Serious TEAEs occurred in 16.0%, 16.9%, and 18.9%
in patients treated with placebo, safinamide 50 mg/day,
and safinamide 100 mg/day, respectively.
Pyrexia
21 (12.0)
22 (11.6)
15 (8.3)
Asthenia
21 (12.0)
14 (7.4)
21 (11.7)
Fall
17 (9.7)
20 (10.6)
15 (8.3)
Hypertension
12 (6.9)
19 (10.1)
18 (10.0)
Headache
13 (7.4)
20 (10.6)
15 (8.3)
Insomnia
11 (6.3)
21 (11.1)
13 (7.2)
Pain
10 (5.7)
8 (4.2)
8 (4.4)
Adverse-event type,
MedDRA preferred term
Placebo
(n=175)
Safinamide Safinamide
50 mg/day 100 mg/day
(n=189)
(n=180)
Fall
2 (1.1)
3 (1.6)
6 (3.3)
Sepsis
3 (1.7)
1 (0.5)
3 (1.7)
Parkinson’s disease
2 (1.1)
2 (1.1)
2 (1.1)
Pyrexia
3 (1.7)
1 (0.5)
1 (0.6)
Cataract operation
2 (1.1)
1 (0.5)
2 (1.1)
Myocardial infarction
0 (0.0)
1 (0.5)
3 (1.7)
Sudden death
1 (0.6)
1 (0.5)
2 (1.1)
Depression
2 (1.1)
1 (0.5)
0 (0.0)
Gastroenteritis
2 (1.1)
1 (0.5)
0 (0.0)
Dyskinesia
2 (1.1)
0 (0.0)
1 (0.6)
Femur fracture
0 (0.0)
2 (1.1)
1 (0.6)
Anemia
1 (0.6)
0 (0.0)
2 (1.1)
Respiratory failure
1 (0.6)
0 (0.0)
2 (1.1)
• Laboratory tests, vital-signs, and electrocardiographic
assessments showed no clinically relevant differences
between treatment groups.
• Other measures including Dyskinesia Rating Scale
scores and patient diary data indicated no worsening
or potential improvement of dyskinesia with
safinamide treatment.
Conclusions
• In this 2-year, prospective, double-blind, placebocontrolled study of PD patients with motor fluctuations
despite optimized L-dopa treatment, safinamide was
generally well tolerated.
• Two-year completion rates were high, despite
polypharmacy for PD in all subjects.
• The observation that dyskinesia was reported as
a TEAE more frequently in the safinamide groups
than in the placebo group may reflect a slight excess
during the first 6 months of treatment.
• Beyond 6 months, there did not appear to be a risk
for dyskinesia relative to placebo, and the risk of
dopaminergic side effects other than dyskinesia was
not increased versus placebo.
References
1. Hauser RA. Eur Neurol. 2009;62(1):1–8.
2. Ahlskog JE, Muenter MD. Mov Disord. 2001;16(3):448–458.
3. Pevarello P, et al. J Med Chem. 1998;41(4):579–590.
4. Caccia C, et al. Neurology. 2006;67(7 Suppl 2):S18–S23.
5. Caccia C, et al. Parkinsonism Relat Disord. 2007;13(Suppl 2):S99.
6. Borgohain R, et al. Parkinsonism Relat Disord. 2009;15(Suppl 2):S115.
7. Meshram CM, et al. Mov Disord. 2010;25(Suppl 2):S302.
8. Johns MW. Sleep 1991;14(6):540–545.
Acknowledgements
This study was funded by Newron and Merck Serono S.A.– Geneva, a branch of Merck
Serono S.A., Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.
The authors thank E. Jay Bienen of the Curry Rockefeller Group (supported by Merck
Serono S.A.– Geneva, Switzerland, a branch of Merck Serono S.A., Coinsins, Switzerland,
an affiliate of Merck KGaA, Darmstadt, Germany) for writing assistance.
Safinamide is in clinical development and is not currently approved by any regulatory
authority, including the European Medicines Agency (EMA) or the US Food and Drug
Administration (FDA).
The Study 018 investigators were:
ITALY: T.P. Avarello, U. Bonuccelli, G. Fabbrini, R. Marconi, L. Morgante, M. Onofrj,
C. Pacchetti, P. Stanzione, F. Stocchi. ROMANIA: O. Bajenaru, A. Bulboaca, A. Campeanu,
D. Chirileanu, D. Muresanu, C. Panea, C.D. Popescu, M. Simu, J. Szasz, M. Ticmeanu.
INDIA: S. Bandishti, R. Bansal, M. Behari, K. Belur, M. Bhatt, R. Borgohain, P. Chakraborty,
S. Charulata, S. Dwivedee, N. Ichoporia, U. Karadan, A. Kishore, S. Kothari, S. Kumar,
A. Kumar Roy, M. Mehndiratta, N. Mehta, C. Meshram, U.K. Misra, J.K. Murthy, A. Pangaria,
S. Prabhakar, S. Pradhan, P. Pal, V. Prasad, C. Prasad Das, M.I. Sahadulla, P.K. Sethi,
A.B. Shah, N. Shankar, R. Shukla, Y. Singh, A. Sowani, R. Srinivasa, A.V. Srinivasan,
C.J. Vaas, M. Varma, D. Vasudevan, C.U. Velmurugendran, K. Vijayan.