Effect of glatiramer acetate three-times weekly on the evolution of new, active multiple sclerosis lesions into T1-hypointense “black holes”: a post hoc magnetic resonance imaging analysis

Abstract

Conversion of active lesions to black holes has been associated with disability progression in subjects with relapsing-remitting multiple sclerosis (RRMS) and represents a complementary approach to evaluating clinical efficacy. The objective of this study was to assess the conversion of new active magnetic resonance imaging (MRI) lesions, identified 6 months after initiating treatment with glatiramer acetate 40 mg/mL three-times weekly (GA40) or placebo, to T1-hypointense black holes in subjects with RRMS. Subjects received GA40 (n = 943) or placebo (n = 461) for 12 months. MRI was obtained at baseline and Months 6 and 12. New lesions were defined as either gadolinium-enhancing T1 or new T2 lesions at Month 6 that were not present at baseline. The adjusted mean numbers of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a negative binomial model; adjusted proportions of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a logistic regression model. Of 1,292 subjects with complete MRI data, 433 (50.3 %) GA-treated and 247 (57.2 %) placebo-treated subjects developed new lesions at Month 6. Compared with placebo, GA40 significantly reduced the mean number (0.31 versus 0.45; P = .0258) and proportion (15.8 versus 19.6 %; P = .006) of new lesions converting to black holes. GA significantly reduced conversion of new active lesions to black holes, highlighting the ability of GA40 to prevent tissue damage in RRMS.

The heritage of glatiramer acetate and its use in multiple sclerosis

“…In a substudy of the PreCISe trial, patients treated with GA had increased brain concentrations of the neuronal integrity marker N-acetylaspartate, and an improvement in brain neuronaxonal integrity, whereas patients receiving placebo did not [47]. Also, magnetic resonance imaging (MRI) studies have demonstrated the ability of GA to reduce the proportion of new T1 hypointense lesions evolving into permanent black holes (markers of irreversible axonal loss), therefore supporting the neuroprotective scenario [48,49].…”

“…An important finding from a recent post hoc MRI analysis of data from the GALA study is that GA 40 mg/mL three times weekly (cumulative weekly dose of 120 mg) shares the ability of the standard formulation (cumulative weekly dose of 140 mg) to reduce conversion of new active lesions into black holes, markers of permanent damage and disability progression, with a significant 24 % reduction compared with placebo (p = 0.006) in the odds of conversion from new lesions at month 6 to black holes at month 12 [49].…”

MRI in the assessment and monitoring of multiple sclerosis: an update on best practice

“…Recent studies, quantifying cord lesions, have found that especially cervical lesions were associated with disability in both relapsing and progressive forms of MS and a higher lesion load was seen in patients with progressive MS. 60 As in RIS, spinal lesions are predictive of developing clinically definite MS from CIS, wherein two thirds of patients with initial nonspinal CIS, having concomitant spinal cord lesions, developed MS after 5 years. 50 T1-hypointense lesions T1-hypointense lesions, so-called 'black holes', are hypointensities that are persistent for 6 months after the initial enhancement 61 and show significant demyelination and axonal loss. 62 Chronic T1-hypointense lesions are closely linked to neurodegeneration and are known to correlate with disability in patients with MS. 63 There is increased interest in the predictive value of T1-hypointense lesions, which are utilized more often as an endpoint for clinical studies.…”

Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis

“…The overall AE profile of patients treated with GA 40 mg TIW was comparable to the experience of the 20-mg daily dosage. An MRI sub-study of participants in the GALA study found that TIW dosing for GA was effective in reducing the conversion of active lesions to black holes, thus showing GA has a favorable effect on tissue disruption in MS lesions [94]. In addition, another related trial by Khan et al included a 24-month extension study of GALA to evaluate outcomes from early treatment initiation compared with delayed treatment in patients who were switched from placebo to GA after the parent trial ended.…”