Two decades of subcutaneous glatiramer acetate injection: current role of the standard dose, and new high-dose low-frequency glatiramer acetate in relapsing–remitting multiple sclerosis treatment

Figures & data

Table 1 Reviewed studies

Article	Patients	Treatment arm	Comparison	Length of follow-up	Main outcome
Pivotal trials
Bornstein et al^Citation38	RRMS	GA 20 mg/day SC (n=25)	Placebo (n=23)	2 years	No relapse in 56% of GA-treated subjects versus 26% in placebo (P=0.045)
Johnson et al^Citation39	RRMS	GA 20 mg/day SC (n=125)	Placebo (n=126)	2 years	29% reduction in relapse rate compared to placebo (P=0.007)
Comi et al^Citation45	RRMS	GA 20 mg/day SC (n=119)	Placebo (n=120)	9 months	Reduced number of GdE lesions compared to placebo (P=0.003)
Comi et al^Citation23	CIS	GA 20 mg/day SC (n=243)	Placebo (n=238)	Up to 36 months	45% reduced risk of conversion to CDMS compared to placebo (HR 0.55, 95% CI 0.40–0.77; P=0.0005)
Extension studies
Johnson et al^Citation40	RRMS	GA 20 mg/day SC (n=99) since study initiation	Placebo (n=104) since study initiation	Johnson et al^Citation39 extended for additional 1–11 months	32% reduction in relapse rate compared to placebo (P=0.002)
Johnson et al^Citation41	RRMS	GA 20 mg/day SC (n=83, end of 6th year) since study initiation	GA 20 mg/day SC after placebo for 30 months (n=86, end of 6th year)	Johnson et al^Citation39 extended to 6 years	No difference in relapse rate between the two groups after placebo-treated patients’ switch to GA
Johnson et al^Citation42	RRMS	GA 20 mg/day SC (n=72, end of 8th year) since study initiation	GA 20 mg/day SC after placebo for 30 months (n=70, end of 8th year)	Johnson et al^Citation39 extended to 8 years	No difference in relapse rate between the two groups after placebo-treated patients’ switch to GA
Ford et al^Citation43	RRMS	At least one dose of GA 20 mg/day SC (n=232)	–	Johnson et al^Citation39 extended to 10 years	Decreased relapse rate from 1.18/year prestudy to approximately 1/5 years during study
Ford et al^Citation44	RRMS	GA 20 mg/day SC (n=100, end of 15th year) since study initiation	–	Johnson et al^Citation39 extended to 15 years	Decreased relapse rate from 1.12/year prestudy to 0.25/year during study 57% stable/improved EDSS
Wolinsky et al^Citation46	RRMS	GA 20 mg/day SC (n=111) since study initiation	GA 20 mg/day SC after placebo for 9 months (n=113)	Comi et al^Citation59 extended for additional 9 months	54% reduction in mean number of GdE lesions in patients switching to GA
Rovaris et al^Citation47	RRMS	GA 20 mg/day SC (n=73) since study initiation	GA or other/no treatment after placebo for 9 months (n=69)	Comi et al^Citation59 extended to a mean of 5.8 years	No difference in MRI measures between the two groups
Head-to-head trials
Mikol et al^Citation48	RRMS	IFNβ-1a 44 μg 3 times/week SC (n=386)	GA 20 mg/day SC (n=378)	96 weeks	No difference in time to first relapse (HR 0.94, 95% CI 0.74–1.21; P=0.64) between the two groups
O’Connor et al^Citation49	RRMS	IFNβ-1b 250 μg/2 days SC (n=888) and 500 μg/2 days SC (n=887)	GA 20 mg/day SC (n=445)	2.0–3.5 years	No difference in relapse risk (P=0.48 and P=0.74) between the groups
Cadavid et al^Citation50	RRMS or CIS	IFNβ-1b 250 μg/2 days SC (n=36)	GA 20 mg/day SC (n=39)	Up to 2 years	No significant difference in combined active lesions (P=0.58) between the two groups
Studies with high-dose GA
Cohen et al^Citation58	RRMS	GA 40 mg/day SC (n=46)	GA 20 mg/day SC (n=44)	9 months	Trend to lower number of GdE lesions in the 40 mg group (38% reduction, P=0.089)
Comi et al^Citation59	RRMS	GA 40 mg/day SC (n=569)	GA 20 mg/day SC (n=586)	12 months	No difference in relapse rate between the two groups (P=0.49)
Khan et al^Citation62	RRMS	GA 40 mg 3 times/week SC (n=943)	Placebo (n=461)	12 months	34% reduction of annual relapse rate compared to placebo (P<0.0001)

Abbreviations: RRMS, relapsing–remitting multiple sclerosis; CIS, clinically isolated syndrome; CDMS, clinically definite multiple sclerosis; GA, glatiramer acetate; SC, subcutaneously; HR, hazard ratio; CI, confidence interval; GdE, gadolinium-enhancing; IFNβ, interferon beta; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging.

Figure 1 Mechanisms of action of glatiramer acetate (GA) in multiple sclerosis. GA exhibits competitive binding at the MHC-II complex and T-cell receptor (TCR) antagonism. GA is able to displace myelin basic protein from the binding site on MHC-II molecules. Treatment with GA leads to the induction of antigen-specific TH2 T cells in the periphery (1). In addition CD8⁺ and CD4⁺CD25⁺ regulatory T cells are induced by GA therapy (2). The constant activation seems to have an important impact on the induction and maintenance of the regulatory/suppressive immune cells (3). Because of the daily activation, GA T cells are believed to be able to cross the blood–brain barrier (4). Inside the central nervous system, some GA-specific T cells cross-react with products of local myelin turnover presented by local antigen-presenting cells (APCs) (5). In response, anti-inflammatory cytokines are secreted, which dampen the local inflammatory process (bystander suppression) (6). Furthermore, GA-specific T cells secrete neurotrophic factors that might favor remyelination and axonal protection (7). Reprinted from Autoimmun Rev. 2007;6(7). Schrempf W, Ziemssen T. Glatiramer acetate: mechanisms of action in multiple sclerosis. 469–475. Copyright © 2007, with permission from Elsevier.⁷⁸

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