Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis

Figures & data

Figure 1 Selection process for published papers.

Note: In addition to papers and abstracts selected, 21 additional references were included for the Introduction and Discussion sections.
Abbreviation: DMTs, disease-modifying treatments.

Table 1 Clinical end points from the fingolimod extension studies

Clinical studies	Patients Enrolled (n, % of ITT)	Patients having completed the study (n, % of ITT)	Mean (SD) exposure to fingolimod, years	Relapse in year prior to study enrollment (mean, SD)	ARR (95% CI)a	Patients free from relapse (%, 95% CI)	Patients free of 6-months confirmed CDP (%, 95% CI)
Phase II long- term extension^Citation20	250 (89)	122 (43)	5.1b		0.17c	60.9d	82d
Phase III FREEDOMS long-term extension^Citation21	920 (72)	773 (61)	3.8 (0.6)e 3.7 (0.6)f	1.5 (0.8)e 1.5 (0.9)f	0.19 (0.16-0.22)e 0.16 (0.14-0.2)f	59.3 (54.2-64.4)e 59.9 (53.9-65.8)f	80 (76-84)e 79 (75-84)f
Phase III TRANSFORMS long-term extension^Citation22	1,027 (79)	772 (60)	3e 2.8f	1.5 (1.3)e 1.5 (0.9)f	0.16 (0.12-0.19)g	NA	NA
Long-term extension of the LONGTERMS^Citation31	3,168	2,767	3.1 (0.2–10.4)	1.2 (1)	0.19	NA	79.3h

Notes:

a Over entire duration of observation period;

b median;

c in patients having received at least 6 months of fingolimod;

d Kaplan–Meier estimates adjusted for dropouts in patients exposed to fingolimod for 6 months at least;

e in continuous fingolimod 0.5 mg group;

f in continuous fingolimod 1.25 mg group;

g between month 13 (beginning of extension phase) and end of study;

h at month 60 for 729 patients.

Abbreviations: ITT, intent to treat; ARR, annualized relapse rate; CDP, confirmed disease progression.

Table 2 Radiological endpoints of fingolimod extension studies

Clinical studies	Mean (95% CI) new or newly enlarging T2 lesions	Mean (95% CI) cumulative GELs	Yearly proportion of patients free from GELs (%)	Yearly proportion of patients without new or enlarging T2 lesions (%)	Mean BVL across study
Phase II long-term extension^Citation20			84–96a	68–88a	−2.8%b
Phase 3 FREEDOMS long-term extension^Citation21	4.5 (4.27–4.68)c 4.0 (3.8–4.21)d	1.1 (0.98–1.23)c 0.8 (0.7–0.94)d			−1.7 (−1.91 to −1.43)c,e −1.6 (−1.88 to −1.4)d,e
Phase 3 TRANSFORMS long-term extension^Citation22			75f	42f	−1.01 (−0.8)g
LONGTERMS^Citation31	0.9h		50h		−0.33i
Long-term extension of the TRANSFORMS study^Citation25	0.8j		50j	35j

Notes:

a Regardless of initial randomization group, yearly percentages from year 1 to year 7;

b calculated over 84 months;

c in continuous fingolimod 0.5 mg group over 48 months;

d in continuous fingolimod 1.25 mg group over 48 months;

e 95% CI;

f for fingolimod 0.5 mg group between month 13 (beginning of extension phase) and end of study;

g SD;

h between months 0 and 60 (n=605)³¹;

i annualized rate of BVL between months 0 and 60 (n=548)³¹;

j between months 0-60 (n=924).²⁵

Abbreviations: GELs, gadolinium-enhancing lesions; BVL, brain-volume loss.

Table 3 FU and treatment-discontinuation rates in Phase III clinical trials and the LONGTERMS extension

Patient disposition		FREEDOMS^Citation17	FREEDOMS2^Citation19	TRANSFORMS^Citation18	LONGTERMS 10-year FU^Citation31
ITT (n)		425	358	429	3,168
Patients having completed FU (n, %)		369 (87)	272 (76)	398 (93)	2,767 (87)
Patients having discontinued drug (n, %)	Total	80 (19)	116 (32)	44 (10)	401 (13)
Reason for drug discontinuation (n, %)	Adverse events	15 (19)a	35 (30)a	16 (36)a	109 (27)a
	Abnormal laboratory values	20 (25)a	25 (21.5)a	7 (16)a	40 (10)a
	Efficacy	8 (10)a	14 (12)a	5 (11)a	73 (18)a
	Withdrawal of consent	17 (4)	19 (5)	9 (2)	88 (3)
	Lost to FU	6 (1.5)	11 (3)	0	26 (1)

Note:

a Of total number of patients having discontinued the study drug.

Abbreviations: FU, follow-up; ITT, intent to treat.

Table 4 Clinical effectiveness in patients treated with fingolimod for more than 2 years

Clinical studies	n	Mean (SD) exposure to fingolimod, years	Relapse in year prior to study enrollment (mean, SD)	ARRa	Proportion of patients free from relapses, %	Proportion of patients free of 6-month CDP, %b	Cumulative proportion of patients free of clinical disease activity, %c
PANGAEA^Citation28	4,016	2.8 (1.7)	1.5 (1.2) in 3,939	Y1: 0.43 Y2: 0.33 Y3: 0.27 Y4: 0.27 Y5: 0.27	Y1a: 68.6 Y2a: 74.4 Y3a: 78.4 Y4a: 77.5 Y5a: 76	Y1: 89 Y2: 85.6 Y3: 85.2 Y4 : 85.3	Y1: 59.7 Y2: 49.6 Y3: 44.4 Y4: 42.3
Izquierdo et al^Citation29	211	2.7 (2.2)	0.9 (0.8–1)d		Y1: 81 Y2: 69 Y3: 62		Y1: 74 Y2: 58 Y3: 51

Notes:

a Y₁, n=3,363; Y₂, n=2,690; Y₃, n=1,996; Y₄, n=1,139; Y₅, n=474.

b Y₁, n=2,483; Y₂, n=1,913; Y₃, n=1,300; Y₄, n=688.

c Y₁, n=2,670; Y₂, n=2,129; Y₃, n=1,463; Y₄, n=763.

d 95% CI.

Abbreviations: ARR, annualized relapse rate; CDP, confirmed disability progression.

Table 5 AEs of special interest and SAE rates during the Phase III trials, the LONGTERMS extension, and the real-world studies PANGAEA and VIRGILE

Adverse and serious adverse events	Integrated AEs and SAEs in Phase III clinical trials (n=1,640)^Citation17^–^Citation19	LONGTERMS^Citation31 (n=3,168)	PANGAEA^Citation32 (n=3,209)	VIRGILE^Citation33 (n=1,023)
	n (%)
Bradycardia	6 (0.4)	Unk	39 (1.2)	31 (3)
First-degree AV block	26 (2.1)a,b	Unk	7 (0.2)	Unk
Second-degree AV block	1 (0.1)	1 (<0.1)	19 (0.6)	Unk
Myocardial infarction	0	2 (0.1)	0	Unk
Hypertension	74 (6)a	Unk	157 (4.9)	16 (1.6)
Infections (unspecified)		259 (8.2)	Unk	18 (1.8)
Herpes virus infections	76 (6)	Unk	Unk	Unk
Herpes zoster	Unk	64 (2)	80 (2.5)	Unk
PML	0	0	1 (0.03)	Unk
Cryptococcal infection	0	Unk	0	Unk
Fungal	0	23 (0.7)	Unk	Unk
Lymphopenia	196 (12)c	Unk	402 (12.5)	20 (2)
Hepatic enzymes	151 (9.2)d	Unk	183 (5.7)	18 (1)
Macular edema	3 (0.2)	2 (0.1)	17 (0.5)	7 (0.7)
Basal-cell carcinoma	26 (1.6)	18 (0.6)	15 (0.47)	Unk
Other carcinomas	15 (0.9)	8 (0.2)	9 (0.3)	Unk

Notes:

a Calculated from the 1,212 patients on fingolimod 0.5 mg in the Phase III clinical trials (FREEDOMS, FREEDOMS2, and TRANSFORMS);

b 22 of the 26 events were classified as SAEs during the Phase III trials;

c number of AEs, of which three (0.2%) were classified as SAEs;

d number of AEs of which none was classified as an SAE.

Abbreviations: AEs, adverse events; AV, atrioventricular; PML, progressive multifocal leukoencephalopathy; SAE, serious AE; Unk, unknown.

Table 6 Adverse events during first-dose heart-rate monitoring

Heart rate abnormalities		FIRST (n=2,415)^Citation44	START (n=6,998)^Citation45	PANGAEA (n=3,209)^Citation32
First-dose monitoring	Bradycardia (<45 bpm)	15 (0.6%)	63 (0.9%)a	39 (1.22)c
	First-degree AV block (PR >200 ms)	NA	308 (4.5%)b	7 (0.22%)c
	Second-degree AV block, Mobitz I	30 (1.3%)	117 (1.67%)	19 (0.59%)c
	Second-degree AV block, Mobitz II	0	0
	Type 2:1 AV block	13 (0.5%)	43 (0.61%)	NA
	QTc interval >500 ms	0	0	3 (0.09%)c

Notes:

a Four were symptomatic;

b 123 (1.78%) patients had asymptomatic first-degree AV block on the ECG performed 1 week after initiating fingolimod treatment;

c timing of these adverse events was not communicated.

Abbreviations: AV, atrioventricular; PR, pulse rate; NA, not available.

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