Limits...
Equivalent Gene Expression Profiles between Glatopa™ and Copaxone®.

D'Alessandro JS, Duffner J, Pradines J, Capila I, Garofalo K, Kaundinya G, Greenberg BM, Kantor D, Ganguly TC - PLoS ONE (2015)

Bottom Line: Comparative analysis was also performed on sets of transcripts relevant to T-cell biology and antigen presentation, among others that are known to be modulated by glatiramer acetate.No statistically significant differences were observed between Copaxone and Glatopa in the expression levels (magnitude and direction) of these glatiramer acetate-regulated genes.In conclusion, multiple methods consistently supported equivalent gene expression profiles between Copaxone and Glatopa.

View Article: PubMed Central - PubMed

Affiliation: Momenta Pharmaceuticals, Inc., Cambridge, MA, United States of America.

ABSTRACT
Glatopa™ is a generic glatiramer acetate recently approved for the treatment of patients with relapsing forms of multiple sclerosis. Gene expression profiling was performed as a means to evaluate equivalence of Glatopa and Copaxone®. Microarray analysis containing 39,429 unique probes across the entire genome was performed in murine glatiramer acetate--responsive Th2-polarized T cells, a test system highly relevant to the biology of glatiramer acetate. A closely related but nonequivalent glatiramoid molecule was used as a control to establish assay sensitivity. Multiple probe-level (Student's t-test) and sample-level (principal component analysis, multidimensional scaling, and hierarchical clustering) statistical analyses were utilized to look for differences in gene expression induced by the test articles. The analyses were conducted across all genes measured, as well as across a subset of genes that were shown to be modulated by Copaxone. The following observations were made across multiple statistical analyses: the expression of numerous genes was significantly changed by treatment with Copaxone when compared against media-only control; gene expression profiles induced by Copaxone and Glatopa were not significantly different; and gene expression profiles induced by Copaxone and the nonequivalent glatiramoid were significantly different, underscoring the sensitivity of the test system and the multiple analysis methods. Comparative analysis was also performed on sets of transcripts relevant to T-cell biology and antigen presentation, among others that are known to be modulated by glatiramer acetate. No statistically significant differences were observed between Copaxone and Glatopa in the expression levels (magnitude and direction) of these glatiramer acetate-regulated genes. In conclusion, multiple methods consistently supported equivalent gene expression profiles between Copaxone and Glatopa.

No MeSH data available.


Related in: MedlinePlus

Visual comparisons between Copaxone, Glatopa and ACN treatment groups based on all probes.A: The MDS plot shows separation between glatiramer acetate (GA; Copaxone or Glatopa) and media, separation between ACN and media, and no separation between Copaxone and Glatopa. B: Hierarchical clustering yields separation between GA (Copaxone or Glatopa) or ACN and media and no separation between Copaxone and Glatopa. C: Box plot of principal component analysis (PCA) component 1. Includes samples from media control, Copaxone, Glatopa, and ACN.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608686&req=5

pone.0140299.g005: Visual comparisons between Copaxone, Glatopa and ACN treatment groups based on all probes.A: The MDS plot shows separation between glatiramer acetate (GA; Copaxone or Glatopa) and media, separation between ACN and media, and no separation between Copaxone and Glatopa. B: Hierarchical clustering yields separation between GA (Copaxone or Glatopa) or ACN and media and no separation between Copaxone and Glatopa. C: Box plot of principal component analysis (PCA) component 1. Includes samples from media control, Copaxone, Glatopa, and ACN.

Mentions: Results presented in Tables 2 and 3 demonstrate that gene expression responses to Copaxone and Glatopa were not significantly different even though probes utilized to test for such response are sensitive enough to distinguish between GA (Copaxone or Glatopa) and a nonequivalent glatiramoid (ACN). To investigate whether any gene expression differences outside of Copaxone response might exist between Copaxone and Glatopa, all transcripts were considered rather than only those responsive to Copaxone. Statistical results are presented in Fig 4. Fig 4A shows that there is no overrepresentation of small t-test P-values when comparing Copaxone and Glatopa, and this was confirmed by no q-value less than 0.99 for this group comparison. A more stringent statistical evaluation, one which takes into account coexpression between genes, was obtained by using multivariate statistic t; Fig 4B shows no statistically significant difference between Copaxone and Glatopa based on all probes (P = 0.38). Fig 5 provides visual illustrations for the lack of significant difference between Copaxone and Glatopa based on all probes. The MDS plot (Fig 5A) shows clear separation between media and GA (Copaxone or Glatopa) but no separation between Copaxone and Glatopa, while samples corresponding to ACN treatment tend to fall between media and GA samples. Likewise, hierarchical clustering (Fig 5B) yields clear separation between media and GA but no obvious separation between Copaxone and Glatopa. Unlike MDS, hierarchical clustering does not suggest separation of ACN samples from GA-treated samples. Fig 5C shows the results of PCA. The media-only control groups were well separated from the GA groups. Comparison of the mean level of principal component 1 between the media-only control group and each treatment group indicated P < 0.001 (t-test). Copaxone and Glatopa could not be distinguished from each other (P = 0.911). To summarize the findings of multiple multivariate statistical analysis methods, using appropriate permutation control, there were no significant difference between Copaxone and Glatopa; however, these same analysis methods indicated differences between Copaxone and ACN.


Equivalent Gene Expression Profiles between Glatopa™ and Copaxone®.

D'Alessandro JS, Duffner J, Pradines J, Capila I, Garofalo K, Kaundinya G, Greenberg BM, Kantor D, Ganguly TC - PLoS ONE (2015)

Visual comparisons between Copaxone, Glatopa and ACN treatment groups based on all probes.A: The MDS plot shows separation between glatiramer acetate (GA; Copaxone or Glatopa) and media, separation between ACN and media, and no separation between Copaxone and Glatopa. B: Hierarchical clustering yields separation between GA (Copaxone or Glatopa) or ACN and media and no separation between Copaxone and Glatopa. C: Box plot of principal component analysis (PCA) component 1. Includes samples from media control, Copaxone, Glatopa, and ACN.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608686&req=5

pone.0140299.g005: Visual comparisons between Copaxone, Glatopa and ACN treatment groups based on all probes.A: The MDS plot shows separation between glatiramer acetate (GA; Copaxone or Glatopa) and media, separation between ACN and media, and no separation between Copaxone and Glatopa. B: Hierarchical clustering yields separation between GA (Copaxone or Glatopa) or ACN and media and no separation between Copaxone and Glatopa. C: Box plot of principal component analysis (PCA) component 1. Includes samples from media control, Copaxone, Glatopa, and ACN.
Mentions: Results presented in Tables 2 and 3 demonstrate that gene expression responses to Copaxone and Glatopa were not significantly different even though probes utilized to test for such response are sensitive enough to distinguish between GA (Copaxone or Glatopa) and a nonequivalent glatiramoid (ACN). To investigate whether any gene expression differences outside of Copaxone response might exist between Copaxone and Glatopa, all transcripts were considered rather than only those responsive to Copaxone. Statistical results are presented in Fig 4. Fig 4A shows that there is no overrepresentation of small t-test P-values when comparing Copaxone and Glatopa, and this was confirmed by no q-value less than 0.99 for this group comparison. A more stringent statistical evaluation, one which takes into account coexpression between genes, was obtained by using multivariate statistic t; Fig 4B shows no statistically significant difference between Copaxone and Glatopa based on all probes (P = 0.38). Fig 5 provides visual illustrations for the lack of significant difference between Copaxone and Glatopa based on all probes. The MDS plot (Fig 5A) shows clear separation between media and GA (Copaxone or Glatopa) but no separation between Copaxone and Glatopa, while samples corresponding to ACN treatment tend to fall between media and GA samples. Likewise, hierarchical clustering (Fig 5B) yields clear separation between media and GA but no obvious separation between Copaxone and Glatopa. Unlike MDS, hierarchical clustering does not suggest separation of ACN samples from GA-treated samples. Fig 5C shows the results of PCA. The media-only control groups were well separated from the GA groups. Comparison of the mean level of principal component 1 between the media-only control group and each treatment group indicated P < 0.001 (t-test). Copaxone and Glatopa could not be distinguished from each other (P = 0.911). To summarize the findings of multiple multivariate statistical analysis methods, using appropriate permutation control, there were no significant difference between Copaxone and Glatopa; however, these same analysis methods indicated differences between Copaxone and ACN.

Bottom Line: Comparative analysis was also performed on sets of transcripts relevant to T-cell biology and antigen presentation, among others that are known to be modulated by glatiramer acetate.No statistically significant differences were observed between Copaxone and Glatopa in the expression levels (magnitude and direction) of these glatiramer acetate-regulated genes.In conclusion, multiple methods consistently supported equivalent gene expression profiles between Copaxone and Glatopa.

View Article: PubMed Central - PubMed

Affiliation: Momenta Pharmaceuticals, Inc., Cambridge, MA, United States of America.

ABSTRACT
Glatopa™ is a generic glatiramer acetate recently approved for the treatment of patients with relapsing forms of multiple sclerosis. Gene expression profiling was performed as a means to evaluate equivalence of Glatopa and Copaxone®. Microarray analysis containing 39,429 unique probes across the entire genome was performed in murine glatiramer acetate--responsive Th2-polarized T cells, a test system highly relevant to the biology of glatiramer acetate. A closely related but nonequivalent glatiramoid molecule was used as a control to establish assay sensitivity. Multiple probe-level (Student's t-test) and sample-level (principal component analysis, multidimensional scaling, and hierarchical clustering) statistical analyses were utilized to look for differences in gene expression induced by the test articles. The analyses were conducted across all genes measured, as well as across a subset of genes that were shown to be modulated by Copaxone. The following observations were made across multiple statistical analyses: the expression of numerous genes was significantly changed by treatment with Copaxone when compared against media-only control; gene expression profiles induced by Copaxone and Glatopa were not significantly different; and gene expression profiles induced by Copaxone and the nonequivalent glatiramoid were significantly different, underscoring the sensitivity of the test system and the multiple analysis methods. Comparative analysis was also performed on sets of transcripts relevant to T-cell biology and antigen presentation, among others that are known to be modulated by glatiramer acetate. No statistically significant differences were observed between Copaxone and Glatopa in the expression levels (magnitude and direction) of these glatiramer acetate-regulated genes. In conclusion, multiple methods consistently supported equivalent gene expression profiles between Copaxone and Glatopa.

No MeSH data available.


Related in: MedlinePlus