Review of the clinical evidence for interferon β 1a (Rebif^®) in the treatment of multiple sclerosis

Figures & data

Table 1 Post-marketing studies characteristics

Study	FU years	Clinical outcomes	Characteristics of the study	Number of patients and treatment
Bonavita et al 2006	2	– Reduction in relapse rate – OR for remaining relapse free – Change of EDSS score – OR for remaining progression free	Observational, retrospective	58 A, 42 B, 48 R 22, 67 R 44
Results
Patients in R 44 more likely to remain free from relapses OR = 2.23
Etemadifar et al 2006	2	– Mean relapse rate – Percentage of patients remaining relapse free after 2 years – Change of EDSS score	Prospective, randomized, assessor-blinded	30 A 30 B 30 R 44
Results
Mean relapse rate decreased in all groups (lower in B and R 44 groups compared to A group) Percentage of patients remaining relapse free after 2 years (A 20%, B 43%, R 44 56%) EDSS change (A stable, B 0.7 U reduction, R 0.3 U reduction)
Haas et al 2005	2	– Relapse rate – number of relapse-free patients – mean EDSS change – progression rate (EDSS change ≥ 1)	Observational, retrospective	A,B,R 22,C Number of patients who reached 2 year FU per each group is not specified
Results
All groups showed sustained reduction of relapse rate, high percentage of relapse-free patients and reduced progression index No superiority of one of the INFβ preparations except for highest relapse-rate decline after 24 months in the C group and progression index significantly lower in R 22 and C groups compared with B group
Kock-Henriksen et al 2006	2	– annualized relapse rate – time to first relapse – time to sustained progression	Open-label, prospective,randomized	188 B 110 R 22
Results
No superiority of one of the INFβ preparations in any of clinical outcomes
Limmroth V et al 2007	2	– Change from baseline EDSS score – percentage of progression-free patients (<1.0 EDSS score) – annualized relapse rate – percentage of relapse-free patients	Observational, retrospective	As initial therapy A 1469, B 1484, R22 784, R44 254 As FU therapy A 224, B 182, R 22 126 R 44 130 (after another DMT they had received for less than 2 years)
Results
No significant differences among IFNs β when used as initial or FU therapy on almost all outcome variables (percentage of progression-free patients lower in R 44 group, but R 44 was used more often as FU treatment, in patients with a likely higher disease activity)
Milanese et al 2005	1–3	– annual relapse frequency com pared to pre-treatment values – EDSS change	Observational,retrospective	115 A, 67 B, 45 R22, 18 R44, 49 C
Results
Annual relapse frequency compared to pre-treatment values decreased by 63%, 67%, 40%, 58%, and 32% in A, B, R22, R44 and C after 1 year and continued to decrease in the subsequent years (81%,86%, 79%, 79%, and 76% respectively after 5 years) EDSS does not consistently change in any treatment group
Paolillo et al 2002	6	– Mean annual relapse rate compared with the 2-year period before treatment – sustained progression defined as an increase of at least 1 Point in EDSS scores 6 months apart	Observational, retrospective 68 patients	All received R for the first 2 years at different doses – 16 continued with R 33 μg t.i.w – 52 continued with B – 11 drop-outs
Results
Mean annual relapse rate compared with the 2 year period before treatment reduced (68.6%) Sustained progression:60% of patients remain stable or improved
Rìo et al 2005	8	– proportions of relapse-free patients – relapse rate compared to 2 years before treatment – probability of remaining progression free	Observational, retrospective	At year 5 A 37 B 114 R 17 (dose not specified)
Results
No differences between the different products were observed
Trojano et al 2005	3–6	– Relapse rate – EDSS change from baseline	Observational, retrospective	395 A, 294 B, 397 R 22, 87 R 44
Results
All groups showed significant reduction in relapse rate (differences between groups not significant) All groups showed increased EDSS change from baseline after 2 years (increase higher in B group)

Abbreviations: A, Avonex; B, Betaferon, Betaseron; EDSS, expanded disability status scale; R 22, Rebif 22 μg, R 44 Rebif 44 μg; C, Copaxone; DMT, disease-modifying treatment; FU, follow-up; OR, odds ratio; RRMS, relapsing-remitting multiple sclerosis.

Table 2 Summary of trials with IFN β 1 a 22 μg and 44 μg in the different indications

CIS	ETOMS
Primary outcome	Proprortion of patient developing CDMS reduced in IFN β 1a group compared to placebo group (34% vs 45%); p = 0.047
Secondary clinical outcomes	Time at which 30% of patients had converted to CDMS longer for IFN β 1a group compared to placebo group (569 vs 252 days) p = 0.034
	Annual relapse rate reduced in IFN β 1a group compared to placebo group (0.33 vs 0.43) p = 0.045
Secondary MRI outcomes	Median number of active T2 lesion per patient per scan reduced in IFN β 1a group compared to placebo group (2.0 vs 3.0) p < 0.001
	Median absolute change in T2 lesion volume (mm^3) reduced in IFN β 1a group compared to placebo group (−487 vs −299) p = 0.002
RRMS	PRISMS
Primary outcome	Relapse rate at year 2 lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (1.82, 1.73 vs 2.56) p < 0.005
Secondary clinical outcomes	Percentage relapse free patients over 1 year higher in IFN β 1a 22 μg and 44 μg groups compared to placebo (37%, 45% vs 22%) p < 0.005
	Percentage relapse free patients over 2 years higher in IFN β 1a 22 μg and 44 μg groups compared to placebo (27%, 32% vs 16% placebo) p ≤ 0.05 and p < 0.005
	Mean moderate or severe relapses in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.71, 0.62 vs 0.99) p < 0.005
	Mean steroid courses lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.97, 0.75 vs 1.39) p ≤ 0.05 and p < 0.005
	Mean hospital admissions lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.38, 0.25 vs 0.48) p < 0.005 only for IFN β 1a 44 μg group compared to placebo
	Mean changes in EDSS lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.23, 0.24 vs 0.48) p ≤ 0.05
Secondary MRI outcomes	Median lesion volume percentage change over baseline lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (−1.2%, −3.8% vs +10.9%) p < 0.0001
	Median number of active lesions lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (−67%, −78%) p < 0.0001
SPMS	SPECTRIMS
Primary outcome	Time to confirmed progression in disability not significantly affected by treatment with IFN β 1a 44 μg compared to placebo (HR 0.83; 95 CI 0.65-1.07) p = 0.146
Secondary clinical outcomes	Mean relapse rate lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.50, 0.50 vs 0.71) p < 0.001 Median time to first exacerbation longer in the IFN β 1a 44 μg group compared to placebo (494 vs 281 days, HR 0.77) p = 0.034
	Median time between first and second exacerbation lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (572, 511 vs 279 days) p ≤ 0.001
	Mean moderate and severe exacerbations per person-year lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.26, 0.27 vs 0.39) p = 0.002, p = 0.003
	Mean steroid courses lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.31, 0.34 vs 0.52) p = 0.001 and p = 0.006
	Mean hospital admission lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.14, 0.15 vs 0.22) p = 0.006 and p = 0.005
Secondary MRI outcomes	Lesion burden change over three years in IFN β 1a 22 μg and 44 μg groups compared to placebo (−32,−4 vs +263) p < 0.001
	T2 active lesions/patient/scan lower in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.17, 0.20 vs 0.60) p < 0.001
	Median CU active lesions/patient/ in IFN β 1a 22 μg and 44 μg groups compared to placebo (0.11, 0.22 vs 1.0) p < 0.001 and p < 0.01

Abbreviations: CIS, clinically isolated syndrome; CI, confidence interval 95%; CDMS, clinically definite multiple sclerosis; CU, combined unique; ETOMS, Early Treatment Of Multiple sclerosis Study group; HR, hazard ratio; PRISMS, Prevention of Relapses and disability by Interferon β-1a Subcutaneously in Multiple Sclerosis; RRMS, Relapsing Remitting Multiple Sclerosis; SPMS, Secondary Progressive Multiple Sclerosis; SPECTRIMS, Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS.

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