Glance

Abstract

Objective: To evaluate the safety and tolerability of natalizumab when added to glatiramer acetate (GA) in patients with relapsing multiple sclerosis. The primary outcome assessed whether this combination would increase the rate of development of new active lesions on cranial MRI scans vs GA alone. Methods:This phase 2, randomized, double-blind, placebo-controlled study included patients aged 19 to 55 years who were treated with GA for at least 1 year before randomization and experienced at least one relapse during the previous year. Patients received IV natalizumab 300 mg (n ϭ 55) or placebo (n ϭ 55) once every 4 weeks plus GA 20 mg subcutaneously once daily for Յ20 weeks. Results:The mean rate of development of new active lesions was 0.03 with combination therapy vs 0.11 with GA alone (p ϭ 0.031). Combination therapy resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p ϭ 0.020) and new/newly enlarging T2-hyperintense lesions (0.5 vs 1.3, p ϭ 0.029). The incidence of infection and infusion reactions was similar in both groups; no hypersensitivity reactions were observed. One serious adverse event occurred with combination therapy (elective hip surgery). With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone. Conclusion:The combination of natalizumab and glatiramer acetate seemed safe and well tolerated during 6 months of therapy. Neurology Interferon ␤ (IFN␤) and glatiramer acetate (GA) are only partially effective for treatment of relapsing multiple sclerosis (MS); approximately two-thirds of patients continue to experience relapses on these therapies over 2 years.1-4 New focal inflammatory lesions in MS are believed to occur when activated T cells cross the blood-brain barrier and initiate a series of events leading to activation of endothelial cells, recruitment of additional lymphocytes and monocytes, release of proinflammatory cytokines, and subsequent demyelination and formation of MS plaques. 5The interaction of ␣ 4 ␤ 1 integrin on leukocytes with vascular cell adhesion molecule 1 on brain endothelial cells is a critical step in migration of leukocytes across the blood-brain barrier. [6][7][8] Natalizumab binds to the ␣ 4 subunit of ␣ 4 ␤ 1 integrin, thereby inhibiting leukocyte trafficking into the CNS (by blocking interactions with molecules including the CS-1 fragment of fibronectin and vascular cell adhesion molecule 1) and potentially altering cell-cell interactions and T-cell activation. [9][10][11]

Interferon Beta and Glatiramer Acetate Therapy

“…As previously described, combination with IFNB-1a IM in the CombiRx study failed to demonstrate benefit in ARR compared to GA alone [53]. In the phase 2 randomized, double-blind, placebo-controlled 24-week Glatiramer Acetate and Natalizumab Combination Evaluation (GLANCE) study, natalizumab (NTZ) was added to RRMS patients with EDSS 0-5 who had been on GA for at least 12 months and had at least one relapse in that time [95]. All 110 participants remained on GA and were either randomized to receive NTZ (n055) or placebo (n0 55) in addition.…”

The heritage of glatiramer acetate and its use in multiple sclerosis

“…Combination treatment trials Two important combination therapy trials are the CombiRx trial [84] and the GLANCE trial [85] (Table 1). In CombiRx, patients were randomised to GA 20 mg/mL once daily plus IFN-β1a 30 μg once weekly or to monotherapy with one of these medications plus placebo for 3 years.…”

Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS

“…4 While factors that stratify natalizumab-associated PML risk, particularly anti-JC virus antibody status, have been identified, 5 the potential efficacy advantage of natalizumab specifically as first-line therapy over other DMTs has not been fully explored. Placebo-controlled trials such as AFFIRM 1 and those comparing natalizumab as an adjunct therapy to interferon-b (IFN-b) and glatiramer acetate (GA) vs IFN-b or GA monotherapy [6][7][8] do not provide information on outcomes associated with initiating natalizumab monotherapy vs other treatment options commonly considered in clinical practice. There are no head-to-head clinical trials comparing the efficacy of first-line natalizumab treatment to other first-line DMTs.…”