Researchers from Teva Pharmaceuticals and Immuneering have developed and published in PLOS One a computational approach for comparing and assessing the biological impacts of branded and generic drugs.
This particular study, which Teva commissioned and funded, compares differences in cells' response to Teva's formulation of glatiramer acetate (GA) — a drug approved by the US Food and Drug Administration for reducing the frequency of relapses in multiple sclerosis cases — as well as a rival product marketed by Hyderabad, India-based Natco Pharma.
However, the methods that the paper describes "can be utilized in a variety of situations to compare the biological impacts of other branded and generic therapies," the researchers wrote, adding that such side-by-side comparisons "can help physicians and regulators take appropriate steps to ensure safety and efficacy."
The pipeline is composed of various statistical tools that are used to analyze gene expression data from cells that have been exposed to the drugs being tested, to determine if the observed profiles were the result of "random variation, or point to consistent differences in biological impact of the generic compared to the branded medicine." It uses techniques such as variance ratio analysis, Anova-based pattern matching, F-tests, and parametric and non-parametric methods to compare "the variability of samples in expression of certain genes" and to evaluate the differences in the "immunological impacts" brought on by the medicines being tested.
The researchers used mouse white blood cells for the PLOS One study, exposing them to Copaxone, the brand name version of GA which Teva packages and sells; and Glatiramer, Natco's generic alternative.
According to Teva, the study revealed "a predictable and therapeutically aligned impact of Copaxone on genes associated with key immune response-related cells … in contrast to a significantly different and irregular impact on genes associated with these cells by the … generic GA."
The researchers found, for example, that Copaxone increased levels of FOXP3 — an immune response protein involved in the development and function of regulatory T cells that may curb autoimmunity in MS patients — "more consistently and effectively" than Natco's Glatiramer. In addition, they found other genes linked to helpful T cells that were "increased to a greater extent by Copaxone relative to the purported generic GA" although the company noted in a statement that the degree to which these changes affect patients' response remains unknown.
Also compared to Copaxone, Natco's Glatiramer increased gene expression in myeloid lineage cells, such as monocytes, which a separate study shows "are 'prominent contributors' to neuroinflammation in MS," the authors wrote. However, the company noted in its statement that "without clinical trials, the extent to which the increased impact of … generic GA on myeloid lineage cells might alter clinical outcomes in [relapse-remitting multiple sclerosis] patients remains unknown."
The researchers also found inconsistencies in drug samples that were selected from different batches of generic GA compared to samples selected from multiple Copaxone batches. According to the paper, they analyzed 34 drug samples from 30 different Copaxone batches and found these to be "highly consistent." In contrast, they found higher levels of variability in 11 samples collected from five batches of Glatiramer.
Michael Hayden, Teva's CSO and president of global research and development and a co-author on the study, said in statement that the findings suggest "a distinct potential difference in the impact of a purported generic GA on the immune system of patients, with possible implications on efficacy and safety in RRMS patients" that can only be properly elucidated and understood "by conducting a full battery of clinical studies."
More broadly, "the data analysis methods described here can be utilized in a variety of situations to compare the biological impacts of other branded and generic therapies, in order to ensure that patients receive the best possible medicines," the researchers wrote in PLOS One.