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confirming the safety profile of GA in long-term treatment.


GA was also investigated in a multinational Phase III trial (PreCISe); the primary endpoint was the time to conversion to clinically definite (CD) MS, and the secondary endpoint was MRI measures. GA was significantly more effective than placebo in delaying the conversion to CDMS (p=0.0005) with a relative reduction in the risk of converting to CDMS of 45% (hazard ratio (HR) 0.55; 95% CI 0.44–0.77). Moreover, GA patients showed fewer new T2 lesions than placebo, whereas there was no significant difference in the percentage change of brain volume between groups.3 In three multicentre studies, GA was also compared in terms of efficacy and safety with IFN-β, another first-line therapy in MS.23-25


Both clinical and MRI


parameters were considered as principal outcomes.


In the REGARD study, GA was compared with IFN-β1a administered sc and showed no differences between the two groups in terms of ARR and proportion of relapse-free patients.23


IFN-β1a group had a lower number of gadolinium-enhancing (Gde) lesions compared with the GA group, although the latter showed significantly less brain atrophy than the IFN group.23


In the


BEYOND study, ARRs with GA and IFN-β1b sc 500µg were 0.34 and 0.33, respectively, and the proportions of relapse-free patients were 59 and 60%, respectively.24


The European/Canadian MRI study was a placebo-controlled study, and a long-term, open-label extension phase after nine months.25


volumes.28


Moreover, both combination therapy and GA were more effective than IFN in reducing the risk of relapse over three years. However, the combination did not reduce disease progression or the change in multiple sclerosis functional composite (MSFC) measure over three years.28


Khan et al explored the efficacy and safety of GA administered three times a week compared with placebo. A 34% reduction in RR for GA-treated patients and a significant reduction in T2 lesion load (34.7%) and Gde lesions (44.8%) was noted.29


Safety and tolerability


GA has shown a good safety profile and most adverse events were of mild to moderate severity. These data were confirmed in placebo-controlled trials and active comparator trials.23


The


Common adverse effects are often immediate, lasting up to 30 min and resolving spontaneously. These include: post-injection systemic reaction, including flushing; palpitations/ tachycardia; dyspnoea; anxiety; urticaria; constriction of the throat; and chest pain. The most frequent adverse events are injection site reaction such as itching, swelling, pain and redness.


Adherence is an important issue when considering drug tolerability.30


The Early GA treatment


showed a significantly reduced T2- weighted lesion burden on MRI scans compared with delayed GA treatment, while at a mean of 5.8 years after randomisation, 63% of the patients enrolled in the study, returning for a long-term follow-up visit, showed no significant differences in MRI measures.26 However, patients in the early treatment group were significantly less likely to require a walking aid than patients who received GA after a nine-month delay.27 A three-arm, randomised, double- blind, placebo-controlled, multicentre, Phase III trial of combination therapy utilising IFN + GA or each single agent with matching placebo (CombiRx) showed the combination to be better than either agent alone in reducing new lesion activity and accumulation of total lesion


adherence to injectable disease-modifying treatment has been investigated and has shown that the most frequent reasons for non-adherence in GA-treated patients were forgetting to administer the drug (57.8%) and injection-related reasons (32.9%). In the active comparator studies, both IFN and GA showed a comparable tolerability. The most frequent severe adverse events are lipoatrophy and skin necrosis in the injection site; occurrence can be minimised by rotating the daily injection site and following good injection technique.30


These reactions are more


frequent in patients with a greater mass of subcutaneous adipose tissue.31


A study


has shown a reduced occurrence of injection site reaction, lower pain scores and fewer symptoms with a reduced volume formulation of GA (GA 20mg/0.5ml) compared with the regular volume formulation (GA 20mg/1ml).32 Using a Visual Analog Scale (VAS), patients recorded daily the severity of injection pain immediately and 5 min post-injection, and the presence and severity of injection site reactions within 5 min and 24 h post-injection. Although


injections site reactions were rare for both preparations, the severity of reactions ranked significantly lower and fewer symptoms occurred within 5 min and 24 h of using the reduced volume formulation (p<0.0001).


Generics


The US Food and Drug Administration has approved the first generic GA, Glatopa™, as fully substitutable for all indications for which Copaxone 20mg is approved. Despite its complexity, and without requiring any clinical data, approval was accomplished through an Abbreviated New Drug Application in which equivalence to Copaxone was evaluated across four criteria: starting materials and basic chemistry; structural signatures for polymerisation, depolymerisation, and purification; physicochemical properties; and biological and immunological properties.33


Conclusions


GA is approved as a first-line therapy in RRMS and clinically isolated syndrome patients. Clinical studies have shown GA is effective in reducing ARR in RRMS and delay the conversion of CIS to clinically- definite MS. The drug is characterised by a good safety profile and mild to moderate side effects. New formulations and new copolymers will be developed in the future in order to reduce injection site effects. Indeed, improvements in adherence are linked to a positive impact on patient outcomes. It has been demonstrated that suboptimal adherence is linked to an increased proportion of patients experiencing relapse, to an increased level of disability and to higher cost of care. Clinicians can provide to support patients with a holistic approach including multidisciplinary expertise and services. The goal is to realise interventions to support the patients evaluating case-by-case the range of factors influencing adherence. l


References 1. Lincoln J. An overview of gene-epigenetic- environmental contributions to MS causation. J Neurol Sci 2009;286:54–7.


2. Copaxone (glatiramer acetate) solution for subcutaneous injection: US prescribing information highlights [online]. www.accessdata. fda.gov/drugsatfda_docs/


label/2009/020622s057lbl.pdf (accessed March 2016).


3. Comi G et al. Effect of glatiramer acetate on www.hospitalpharmacyeurope.com 19


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