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generics in terms of biological effects have been carried out. These studies demonstrated that they have significantly more variable biological effects than GA, especially with regard to the activity of immune cells associated with an inflammatory response as shown in the study carried out by Tofic and colleagues.5


GA


addition, more consistently and to a higher extent than the generic, induced regulatory T-lymphocytes, whereas generic GA significantly upregulated myeloid lineage immune cells (monocytes, macrophages). These observed differences seem to have an influence on the clinical efficacy (forkhead box P3-positive regulatory T-cells in MS patients induce tolerance by suppression of T-cells reactive against myelin; monocytes are a major causative of inflammation in MS) and the safety of both drugs.3 Synthon developed another generic – GTR001. The EMA requested clinical investigation to confirm that the new FOGA was therapeutically equivalent to the original GA. The results of this study – GATE (Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone) – have been published.6,7


This was a multinational,


randomised, double-blind, placebo- controlled Phase III trial aimed at demonstrating that the efficacy of GTR001 is the same as that of the


original GA. The study included a total of 794 adult patients with MS (default EDSS score 0–5.5) who were treated with GTR001 (n=353), the original GA (n=357), or placebo (n=84). After completion of nine months of therapy, the study was unblinded, and patients could continue with GTR001 for 15 months (open phase). The primary endpoint of the study was the combined number of T1 gadolinium (Gd)- enhancing lesions after 7–9 months of treatment, Other endpoints included MRI parameters (for example, change in T2 lesion volume), the annual relapse rate, proportion of patients with inactive disease, or changes in EDSS score. It also recorded the incidence of adverse events.


Baseline characteristics of patients in all arms were comparable. The estimated geometric mean of the number of Gd-enhancing lesions was 0.42 (GTR001) versus 0.39 (GA), that is, the ratio of the number of lesions was 1.097 (95% CI 0.884–1.362), which was pre-configured within the range of equivalence. Both drugs were significantly more effective than placebo (p<0.001). The annual relapse rate was 0.31 (GTR001) versus 0.41 (GA) versus 0.39 (placebo). The proportions of patients with inactive disease were comparable in all arms and EDSS score remained stable in all arms. Incidence, range and severity of adverse reactions,


including injection site reactions were similar in both groups.


The authors conclude the study shows that GTR001 is the first generic GA for which equivalent efficacy and safety to the original GA has been demonstrated. However, even if comparable therapeutic equivalence between certain generic GA and GA is demonstrated, further questions remain, for example, regarding converting from GA to generic and interchangeability or changing terminology remain.1,2 l


References 1. Varkony H et al. The glatiramoid class of immunomodulator drugs. Expert Opin Pharmacother 2009;10:657–68.


2. Schellekens H et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J 2014;16:15–21.


3. Schellekens H et al. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol 2011;59:176–83.


4. FDA Citizen Petition 2014. FDA-2014-P-0933. 5. Towfic F et al. Comparing the biological impact of glatiramer acetate with the biological impact of a generic. PLoS One 2014;9:e83757.


6. Cohen J et al. Generic glatiramer acetate is equivalent to Copaxone on efficacy and safety: results of the randomized double-blind GATE trial in multiple sclerosis. 2014 ACTRIMS-ECTRIMS Meeting, abstract FC1.2.


7. Cohen J et al. Equivalence of generic glatiramer acetate in multiple sclerosis. A randomized clinical trial. JAMA Neurol 2015;72(12):1433–41.


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