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Multiple Sclerosis


Figure 3: Kaplan–Meier Curve with Time to Confirmed Disability


Time to confirmed EDSS 4, 6, or 8 while on GA


0.0 0.2 0.4 0.6 0.8 1.0


}


} }


0


510 Years on GA


Modified intention-to-treat cohort (n=232) Ongoing cohort (n=100)


EDSS = expanded disability status scale; GA = glatiramer acetate. Source: Ford et al., 2010.27


treatment duration of 13.6 years. For ongoing patients, the ARR maintained a decline from 1.12 ± 0.82 at baseline to 0.25 ± 0.34 per year. Fifty-seven per cent had stable/improved EDSS scores, 65 % had not transitioned to SPMS, and 82 % remained ambulatory without mobility aids. For all patients on GA therapy (i.e. all those who received at least one dose of GA since study initiation), the ARR declined from 1.18 ± 0.82 to 0.43 ± 0.58, 54 % had stable or improved EDSS scores, and 75 % had not transitioned to SPMS (see Figures 2 and 3). There were no long-term safety issues and the commitment of patients to take daily sc injections for 15 years emphasizes the long-term tolerability and patient acceptance of GA.27


This trial remains the only prospectively designed study to


examine long-term improvements in disability among any of the approved therapies.


Three observational studies have investigated long-term GA use in MS and have provided evidence of inhibition of disability progression.56–59


A


French study involved 205 patients with RRMS who received GA as part of a compassionate-use program. The patients were followed up for 3.5 to eight years, during which time the mean EDSS scores were largely unchanged and only 5.7 % of the patients showed disability progression after five years (defined as an increase of one point in EDSS score after five years).57


An Argentinian study56 used information drawn from a


national registry which gathers information on patients who receive DMDs. Among 174 GA-treated patients, during a six-month duration, approximately 22 % improved by ≥1 EDSS point, 2.5 % were unchanged, and 15 % showed EDSS progression by ≥1 point. The median time from diagnosis to an EDSS score of 6.0 was 15 years for patients receiving GA versus nine years for an untreated cohort of 360 patients. A study in the


1. Goodin DS, Frohman EM, Garmany GP Jr, et al., Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines, Neurology, 2002;58:169–78.


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4. Pugliatti M, Sotgiu S, Rosati G, The worldwide prevalence of multiple sclerosis, Clin Neurol Neurosurg, 2002;104:182–91.


130 15


GA EDSS 8 GA EDSS 6 GA EDSS 4


A majority of patients (57 %) showed either unchanged or improved EDSS scores. Only 10 of 28 (36 %) patients who had baseline EDSS scores <4.0 showed a last observed value of ≥4 and only eight of 34 (24 %) with a baseline EDSS score <6.0 worsened to a score of ≥6.0. These observational studies therefore appear to indicate that in patients receiving long-term treatment at MS treatment centers in different countries, GA had a beneficial inhibitory effect on disability progression compared with concurrent MS patients who were not receiving treatment.


Concluding Remarks 20


Currently, a new generation of MS therapies is emerging, with novel mechanisms of action and new delivery modalities, that include several oral and monoclonal antibody treatments. Although one of the oral medications has recently been approved, it remains unclear whether such therapies will provide patients with a higher standard of long-term efficacy and safety than is provided by the current selection of injectable DMDs. GA is an established DMD with a substantial number of clinical studies, analyses, and experience in the clinic that provide evidence to support its continued use in RRMS. Long-term studies of continuous GA administration up to 15 years show that the medication decreases relapse rates and decreases or stabilizes disability progression. There is also evidence to suggest that early GA therapy can reduce the risk of developing CDMS when given to patients with early-stage disease. In addition, the efficacy of GA in reducing relapse rates has been shown in several studies to contribute to improved adherence, better cost-effectiveness, and greater ability to remain in employment compared with the IFNβ treatments. GA, therefore, is at least as effective as the IFNβs in the early years of treatment, but long-term data suggest that it is more effective if treatment is started earlier in the disease course rather than delaying it. In addition, in several studies GA therapy has proven to be beneficial for patients with MS who switch from IFNβ, or from natalizumab, where patients test positive for JC virus and are at risk of PML. Furthermore, GA has the most favorable safety and tolerability profile of all agents available for the treatment of MS; it is not associated with the influenza-like symptoms characteristic of the IFNβs and is consequently an attractive option for many patients with MS.


GA is therefore likely to continue as a first-line therapy for use in RRMS for the foreseeable future. GA has a complex mechanism of action that is known to modulate immune and inflammatory pathways at several different levels. Although new oral and monoclonal antibody treatments are now emerging for MS treatment, the multiple modes of action that GA exerts on the pathological processes of MS confer substantial efficacy. This efficacy and tolerability in long-term use are factors that are likely to continue to make GA valuable as a mainstay of MS therapy for some years to come. n


5. Bates D, Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials, Neurology, 2011;76:S14–25.


6. Lublin FD, Reingold SC, Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis, Neurology, 1996;46:907–11.


7. Inglese M, Grossman RI, Filippi M, Magnetic resonance imaging monitoring of multiple sclerosis lesion evolution, J Neuroimaging, 2005;15:22S–29S.


8. Stoeckle C, Tolosa E, Antigen processing and presentation in multiple sclerosis, Results Probl Cell Differ, 2009;51:149–72.


9. Hedegaard CJ, Krakauer M, Bendtzen K, et al., T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis, Immunology, 2008;125:161–9.


10. Jadidi-Niaragh F, Mirshafiey A, Th17 cell, the new player of neuroinflammatory process in multiple sclerosis, Scand J Immunol, 2011;74:1–13.


11. Mao YS, Lu CZ, Wang X, Xiao BG, Induction of experimental autoimmune encephalomyelitis in Lewis rats by a viral peptide with limited homology to myelin basic protein,


US NEUROLOGY


US on a smaller group of patients with RRMS (n=46) also included the use of GA on a compassionate-use basis but for much longer durations (up to 22 years).58


Survival distribution function


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