36 month PANGAEA: A 5-year non-interventional study of safety, efficacy
and pharmacoeconomic data for fingolimod patients in daily clinical practice
PND2
T. Ziemssen , Albrecht H , Haas J , Klotz L , Lang M , Lassek C , Schmidt S , Tackenberg B , Cornelissen C 1
2
3
4
5
6
7
8
9
University Clinic Carl Gustav Carus, Dresden, Germany, 2 Praxis für Neurologie München, Munich, Germany, 3 Jüdisches Krankenhaus Berlin, Berlin, Germany, 4 Uniklinik Münster, Münster, Germany, 5 NTD study group, Ulm, Germany,
6
Neurologische Gemeinschaftspraxis Kassel und Vellmar, Kassel, Germany, 7 NTD study group, Bonn, Germany, 8 Philipps-Universität Giessen und Marburg, Marburg, Germany, 9 Novartis Pharma GmbH, Nuremberg, Germany
1
Conclusions •R
egardless of the previous disease modifying therapy, fingolimod significantly suppresses
clinical disease activity.
• Fingolimod demonstrated sustained efficacy in the treatment of RRMS.
Introduction
• Long term therapy with fingolimod has a high treatment persistency.
• The low number of reported adverse events is consistent with previous findings from clinical trials.
• The average fingolimod patient has a stable EDSS.
Figure 3 | Efficacy
Purpose
The PANGAEA registry records data of German patients with RRMS that are treated with fingolimod
under real life conditions for 5 years. Here, we present the results of an interim analysis after
36 months from February 2015.
Methods
PANGAEA is a prospective, multi-center, non-interventional, long-term study of fingolimod (0.5 mg)
for the treatment of patients with RRMS. The observation period under PANGAEA is up to 60 months
with follow-up visits about every 3 months. Patients treated for the first time with fingolimod (n = 3121)
and former study participants (n = 830) are documented in PANGAEA.
a | ARR of the full PANGAEA population and and stratified by selected former disease modifying therapy
Previous disease modifying therapy
Once daily oral fingolimod (FTY720; Gilenya®, Novartis Pharma AG), a sphingosine 1-phosphate
receptor (S1PR) modulator, is approved for the treatment of relapsing remitting multiple sclerosis
(RRMS) in over 80 countries. As of May 2015, it is estimated that Gilenya® has been used to treat
approximately 125,000 patients in clinical trials and the post-marketing setting. The total patient
exposure now exceeds 240,000 patient years. [a]
All PANGAEA patients
1.5
0.43
0.41
0.37
All interferons
1.6
0.43
0.38
0.35
Glatiramer acetate
1.6
0.38
0.39
0.35
1.5
0.35
0.33
0.39
No / other
years [ mean ± SD ]
female [ N ( % ) ]
male [ N ( % ) ]
kg [ mean ± SD ]
cm [ mean ± SD ]
kg/m2 [ mean ± SD ]
Weight
Height
Body mass index
Disease and treatment history
Time since diagnosis
Number of MS relapses within last 12 months
Number of MS relapses within last 24 months
EDSS score
MSSS score
39.1 ± 10.0
2832 (71.8 %)
1115 (28.2 %)
72.2 ± 17.2
171.4 ± 8.7
25.2 ± 5.2
years [ mean ± SD ]
mean ± SD
mean ± SD
mean ± SD
mean ± SD
8.2
1.5
2.2
3.0
5.1
±
±
±
±
±
6.3
1.2
1.7
1.7
2.6
Figure 1a | Previous disease modifying therapy n = 3951
MS relapse activity
Characteristic
Age
Sex
Previous disease modifying therapy
ARR
23.6 %
24.4 %
24.4 %
6.0 %
5.9 %
4.2 %
2 new relapses
2.1 %
1.3 %
1.3 %
> 2 new relapses
1st year (n = 3152)
2nd year (n = 1796)
3rd year (n = 782)
0 20406080
%
c|A
verage change in EDSS of the full PANGAEA population and stratified by
former study participants and first fingolimod treatment in PANGAEA
Treatment duration
Month 24
Month 12
0.30
Month 36
0.20
0.10
0.00
– 0.10
All PANGAEA patients
– 0.20
First fingolimod
treatment in PANGAEA
– 0.03
– 0.12
– 0.15
– 0.30
– 0.07
– 0.15
– 0.19
– 0.13
– 0.40
Former study
participants
– 0.06
– 0.18
0.8
Azathioprin
3rd year (n = 782)
67.9 %
0.43
68.3 %
0.41
70.1 %
1 new relapse
EDSS change
compared to baseline
Table 1 | Baseline characteristics of patients included in this interim analysis
2nd year (n = 1796)
b | MS relapse activity of all PANGAEA patients in year 1 – 3
relapse free
Figure 1 | Baseline demographics
1st year (n = 3152)
00.511.52
Results
A total of 3,951 patients documented up to 36 months at 342 sites were included in this analysis.
The baseline characteristics are described in Table 1 and Figure 1a. Observation period under
PANGAEA was 650.0 ± 372.7 days; average duration of therapy with Gilenya® was 689.4 ± 418.0
days (mean ± SD).
Baseline (n = 3787)
d | Proportion of patients with stable or improved EDSS over a 36 month period
1.3
Mitoxantron
Treatment duration
Month 12 (n = 2317)
Month 36 (n = 404)
100
18.1
Natalizumab
Month 24 (n = 1226)
90
91.3 %
23.0
Glatiramer acetate
80
49.1
70
6.2
None
Missing
1.6
0
10
20
30
40
50
60
Patients [%]
Patients [%]
Interferon
77.1 %
13.7 %
12.3 %
60
50
40
30
20
Safety
77.5 %
10
•R
ates of study discontinuation remained stable with 13.9 % and 12.1 % in years 1 and 2 respectively
(Fig. 2a).
• The proportion of patients who discontinued due to an adverse event reduced from 4.3 % in year
1 to 2.3 % in year 2 (Fig. 2a). The decrease in therapy discontinuation because of adverse events
emphasizes the good long term tolerability of fingolimod therapy.
• Proportion of patients discontinuing treatment due to lack of efficacy or disease progression remained
low at 2.6 % in year 1 and 3.1 % at year 2 (Fig. 2a).
• Within the proportion of patients that discontinued the study documentation, 10.8 % of patients
also discontinued the fingolimod therapy in the first year decreasing to 9.1 % in the second year.
• The safety profile of fingolimod in real life is comparable to that observed in phase III clinical trials.
Table 2 shows an event based listing of all adverse events with a prevalence of more than 2 % (Safety
Analysis Set n = 4001).
Sustained EDSS progression
10.6 %
8.8 %
0
Stable EDSS
4.0 %
Sustained EDSS improvement
4.7 %
Effectiveness and treatment satisfaction
• In the first year of PANGAEA more than 60 % of the patients were disease free defined as patients
without a relapse in the last 12 months and without a sustained EDSS progression (defined by a 6
months stable rise of the EDSS by 1 point for an EDSS ≤ 5.5 or 0.5 points for an EDSS ≥ 6.0) (Fig. 4a).
This proportion increased to 70 % at 3 years and was independent of prior treatment history.
• In a 24 months pharmacoeconomic substudy (n = 449 at baseline) patients were asked to rate
their treatment satisfaction with the Treatment Satisfaction Questionnaire for Medication (TSQM-9;
7 = low satisfaction, 59 = high satisfaction). The total score improved by more than 3 points from
baseline to 36 months (Fig. 4b).
Figure 4 | Disease activity and treatment satisfaction stratified by prior treatment history
Figure 2 | Safety
a | Premature study discontinuation in 1st and 2nd year
Table 2 | Most frequent adverse events
Adverse events with an
occurence of over 2 %
3.6 %
2.6 %
3.4 %
4.3 %
86.1 %
atient
P
continues study
Adverse events
Patient wish
2
nd
year
2.6 %
3.1 %
4.0 %
2.3 %
Therapy related reasons
Other
87.9 %
n [%]
Nasopharyngitis
396 (9.9 %)
Lymphopenia
380 (9.5 %)
Leukopenia
245 (6.1 %)
Lymphocyte count decreased
219 (5.5 %)
Gamma-glutamyltransferase increased
210 (5.3 %)
Hepatic enzyme increased
184 (4.6 %)
Low density lipoprotein increased
173 (4.3 %)
Hypertension
162 (4.1 %)
Headache
155 (3.9 %)
Blood triglycerides increased
146 (3.7 %)
Alanine aminotransferase increased
143 (3.6 %)
Fatigue
134 (3.4 %)
Dizziness
112 (2.8 %)
Depression
103 (2.6 %)
White blood cell count decreased
102 (2.6 %)
Bronchitis
97 (2.4 %)
Transaminases increased
95 (2.4 %)
Urinary tract infection
93 (2.3 %)
Cough
89 (2.2 %)
Back pain
82 (2.1 %)
Vitamin D deficiency
82 (2.1 %)
Efficacy
•T
he average annualized relapse rate (ARR) significantly decreased (p < 0.001) by 71 % from 1.5
(± 0.04, 95 % CI, n = 3787) at baseline to 0.43 (± 0.03, 95 % CI, n = 3152) in the first year of
treatment and remained stable after 3 years of treatment (Fig. 3a).
• Patients previously treated with glatiramer acetate or interferons showed a comparable reduction
of the ARR in the first year of treatment (Fig. 3a): interferons: 73 % reduction of the ARR (baseline:
1.6 ± 0.05, 95 % CI, n = 1882; 1 year: 0.43 ± 0.04, 95 % CI, n = 1550); glatiramer acetate: 76 %
reduction of the ARR (baseline: 1.6 ± 0.07, 95 % CI, n = 896; 1 year: 0.38 ± 0.05, 95 % CI, n = 711).
Again, the therapy with fingolimod showed a sustained efficacy after 3 years.
• More than 67 % of all patients were free of relapses during the first 3 years of PANGAEA (Fig. 3b).
• Patients maintained a stable or improved EDSS over the 3 year period (Fig. 3c; mean value
+/– 95 % CI).
• Over time approximately 80 % of the patients had a stable EDSS. Within the years 1 and 2 of PANGAEA
more than 10 % of the patients showed an at least 6 months sustained improvement of the EDSS
(defined by a 6 months stable decrease of the EDSS by 1 point for an EDSS ≤ 3.0 or 0.5 points for
an EDSS > 3.0) (Fig. 3d).
80 %
70.5 %
61.3 %
70.9 %
70.1 %
64.4 %
Patients [%]
1st year
100 %
60.3 %
64.6 %
63.2 %
66.7 %
60 %
40 %
35.3 %
34.0 %
31.0 %
28.8 %
29.8 %
26.5 %
25.8 %
25.0 %
24.7 %
No disease activity
20 %
6.8 %
4.7 %
0 %
n
1,502
time point
mo. 12
801
4.4 %
3.7 %
265
mo. 24 mo. 36
All patients
1,133
5.8 %
512
5.6 %
3.4 %
143
369
mo. 12 mo. 24 mo. 36
First treatment with Gilenya
Relapse in the last 12 months
8.5 %
4.1 %
289
Sustained EDSS progression
without relapse
122
mo. 12 mo. 24 mo. 36
Former study participants
b | Assessment of fingolimod treatment satisfaction by TSQM-9 questionnaire
54.0
52.1
51.6
52.0
TSQM-9-score
n = 2553 (1st year) | n = 1800 (2nd year)
a | Patients with sustained EDSS progression without relapse and patients with relapse in the last 12 months
51.0
50.1
51.5
50.9
49.9
52.0
51.4
51.2
50.0
50.9
50.6
48.0
46.0
44.0.
47.8
49.5
46.8
Baseline (n = 378)
Month 6 (n = 442)
Month 12 (n = 375)
Month 18 (n = 282)
Month 24 (n = 212)
Treatment duration
All patients
First treatment with Gilenya®
Former study participants
Disclosures
T. Ziemssen has received speaking honoraria and travel expenses for scientific meetings; has been a steering committee member of clinical trials or participated in advisory boards
of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
C. Cornelissen and A. Fuchs are employed by Novartis Pharma GmbH, Germany. H.-J. Schwarz is employed by Kantar Health, Munich.
[a] T
he approved indication may vary from country to country. In the EU, fingolimod is approved for treatment of patients with highly active relapsing-remitting MS. In the United States,
it is approved for the treatment of patients with relapsing forms of MS. Data as of June 30, 2015; Q2 Novartis Pharmaceuticals Interim Financial Report, July 4, 2015.
This study was funded by Novartis Pharma GmbH, Nuremberg, Germany | ISPOR (International Society for Pharmacoeconomics and Outcomes Research)
18th Annual European Congress, 7 – 11 November 2015, Milan, Italy
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