Tuesday, 23 June 2015

COPAXONE by any other name would smell as sweet.

April 28, 2014 Poster Session: MS and CNS Inflammatory Disease: Treatment Mechanisms of Action

Gene Expression Studies Comparing Glatiramer Acetate and Proposed Generics (P1.212)


Benjamin Zeskind, Fadi Towfic, Jason Funt, Kevin Fowler, Shlomo Bakshi, Eran Blaugrund, Sarah Kolitz, Maxim Artyomov, Michael Hayden, Iris Grossman,Liat Hayardeny and Rivka Schwartz

Abstract


OBJECTIVE: Utilize gene expression to compare the biological impact of proposed generics from different manufacturers with each other and with branded glatiramer acetate (GA).

BACKGROUND: Since the 1990s, Copaxone has provided a safe and effective treatment option for MS patients. GA, the active substance of Copaxone, is a copolymer of L-alanine, L-lysine, L-glutamic acid and L-tyrosine. The specific composition of polypeptides in solution comprising GA cannot be fully characterized with available assays. While various physicochemical tests show complete consistency between GA batches, they identify significant differences between GA and proposed generics, as well as amongst proposed generics from different manufacturers. Gene expression provides a means to investigate the biological impact of these differences, particularly given the absence of PK/PD markers for GA. This represents a test case for the broader challenge of assessing biosimilars/biogenerics and generics for non-biological-complex-drugs.

DESIGN/METHODS:Splenocytes from GA-primed mice were reactivated ex-vivo with GA or proposed generics. Expression data were measured using microarrays, and analyzed to identify differentially expressed genes and elucidate underlying biology.

RESULTS: Differentially expressed genes induced by proposed generic vs. GA were associated with activation of inflammatory responses and increased cell adhesion and migration. GA also upregulated FOXP3 and other genes associated with tolerance-inducing regulatory T cells (Tregs) more consistently and to a greater extent than proposed generic. Proposed generic upregulated inflammatory monocyte-related genes to a greater extent than GA. Additional genes differentially expressed between GA vs. proposed generic, and amongst proposed generics from different manufacturers, also may play a role in MS pathology and therapeutic response. Studies in human monocytes are ongoing and will be reported accordingly.

CONCLUSIONS: Gene expression studies identify differences between GA and proposed generics, and differences amongst proposed generics from different manufacturers. These findings warrant further investigation to ensure that MS patients receive safe and effective medicines.

Study Supported by: Teva.

Disclosure: Dr. Zeskind has received personal compensation for activities with Immuneering and Teva Neuroscience. Dr. Towfic has received personal compensation for activities with Immuneering and Teva Neuroscience. Dr. Funt has received personal compensation for activities with Immuneering and Teva Neuroscience. Dr. Fowler has received personal compensation for activities with Immuneering and Teva Neuroscience. Dr. Bakshi has received personal compensation for activities with Teva Neuroscience as an employee. Dr. Blaugrund has received personal compensation for activities with Teva Neuroscience as an employee. Dr. Kolitz has received personal compensation for activities with Immuneering and Teva Neuroscience. Dr. Artyomov has received personal compensation for activities with Immuneering and Teva Neuroscience. Dr. Hayden has received personal compensation for activities with Teva Neuroscience. Dr. Grossman has received personal compensation for activities with Teva Neuroscience as an employee. Dr. Hayardeny Nisimov has received personal compensation for activities with Teva Neuroscience. Dr. Schwartz has received personal compensation for activities with Teva Neuroscience.

Wind forward an year...

April 20, 2015 Poster Session: MS and CNS Inflammatory Diseases: Treatment Mechanisms of Action

Comparative Gene Expression Profiling between a Generic (M356) and Brand Copaxone® (glatiramer acetate injection) (P1.144)


Josephine D’Alessandro, Jay Duffner, Joel Pradines,Christopher Honan, Thomas Prod’homme, Tanmoy Ganguly and Ganesh Kaundinya

Abstract

OBJECTIVE: To contribute to the evaluation of biological equivalence of M356 and Copaxone® by using gene expression profiling studies in T cells using microarrays.

BACKGROUND: M356 is being developed by Momenta and Sandoz as a generic version of Copaxone® for the treatment of relapsing-remitting multiple sclerosis and is under FDA review (as of October 2014). Equivalence between M356 and Copaxone® was evaluated using a comprehensive set of physicochemical (structural) and biological assays.

DESIGN/METHODS: Gene expression changes induced by multiple lots of M356, Copaxone®, and a glatiramoid copolymer (negative control) related to media were examined on murine glatiramer acetate-specific T cells using Agilent 4x44k gene expression microarrays (24,263 different genes). Differences among treatment groups were examined by univariate methods (Student’s t-test; ANOVA) as well as by multivariate methods (principal component analysis and multidimensional scaling) accompanied by the appropriate permutation controls for false positives. In addition, discriminating genes were subjected to gene set enrichment analysis and the level of expression change was examined using T-helper Cell Differentiation Canonical Pathway from Ingenuity Pathway Analysis.

RESULTS: As expected, glatiramer acetate primarily induced Th2-polarized cell expansion and related expression changes, whereas media alone did not. M356 and Copaxone® exhibited similar levels of change in all Th2-relevant transcripts, while the negative control glatiramoid copolymer exhibited significantly different gene expression changes for IL-3 and IL-4 respectively.

CONCLUSIONS: The biologic equivalence of M356 and Copaxone® was demonstrated across gene regulatory effects on T cells. These results were supportive of and consistent with results from a larger biocharacterization program, which consisted of multiple complementary molecular, cell-based, and in vivo assays across relevant biologic activities of glatiramer acetate.

Disclosure: Dr. D’Alessandro has received personal compensation for activities with Momenta Pharmaceuticals. Dr. Duffner has received personal compensation for activities with Momenta Pharmaceuticals. Dr. Pradines has received personal compensation for activities with Momenta Pharmaceuticals, Inc. Dr. Honan has received personal compensation for activities with Momenta Pharmaceuticals. Dr. Prod'Homme has received personal compensation for activities with Momenta Pharmaceuticals, Inc. Dr. Ganguly has received personal compensation for activities with Momenta Pharmaceuticals. Dr. Kaundinya has received personal compensation for activities with Momenta Pharmaceuticals.

Copaxone® or glatiramer acetate is a first line therapy for relapsing-remitting MS produced by Teva Pharamceutical Industries Ltd (NYSE and TASE: TEVA); it is also TEVA's biggest product (grossing $4.2 billion last year alone - 21% of the company's $20.3 billion net revenue). Copaxone® is a random polymer of four amino acids L-glutamic acid, L-lysine, L-alanine, and L-tyrosine found in myelin basic protein. 

So why all the hullabaloo? TEVA's patent is set to foreclose on the 1st of September this year. In January the U.S. Supreme court overturned an appeals court ruling that had invalidated TEVA's patent for Copaxone®. TEVA had argued that Copaxone® was too complex for someone to copy (have another look at the abstracts above). In April, the Food and Drug Administration approved the generic version of Copaxone®, which allows Momenta Pharmaceuticles and the Sandoz unit of Novartis AG, who are collaborating on the generic version: Glatopa, to sell it. In a further appellate review, the U.S. Court of Appeals again ruled TEVA's request as invalid. Hours after the ruling, the first generic version of Copaxone® went on the market last Thursday. The generic version will have a wholesale list price of at least $63,000 a year - eighteen percent cheaper than Copaxone®, hardly cheap I say.

Is disrupting the status quo a laudable goal?

CoI: I have received travel grants from Teva and Novartis, and consultation fees from Novartis. Nada related to Copaxone® or its generics.



8 comments:

  1. Wasn't the point of generics that the consumers would be less financially assraped? Jesus, I could have a master's degree for the amount it would take for me to take Glatopia.

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    Replies
    1. These are biosimilars. However it shows you why companies like biologicals. Copaxone price has been raised massively since its inception. As predicted the price has not fallen significantly. This is not competition but cartels inflating the price.
      You need a real generic.

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  2. And the poster next door http://www.neurology.org/content/84/14_Supplement/P1.145
    Demonstration of Equivalence between a Generic (M356) and Brand Copaxone® (glatiramer acetate injection) (P1.145) James Anderson, et al. they are supported by the manufacturers of M356

    However this approach has been used before on a different generic
    http://multiple-sclerosis-research.blogspot.com/2015/05/are-all-cops-created-equalseems-not.html

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  3. How shocking !! the Teva funded study says we need to test the generics further to make sure thet work ,while the Momenta funded study says that the generics are good to go :O

    Regarding the price tag , are you sure it is 64k a year not for 2 years ?

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    1. Well, I've been following this saga in my own way in the posters, as it often gives you an idea of the arguments and counter-arguments that are being built!
      This is the whole sale price, i.e. the cost price plus the mark up, I'm uncertain as to the retail price - maybe someone who has managed to buy it can let us know?!

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    2. The retail cost is the wholesale/trade sale price plus mark up. The cost of copaxone is about 63,000 on bloomberg, so if 18% less it would be about 55,000.
      Teva have been busy trying to switch people over to the three times a week version which has patent protection until 2030

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    3. There is a logic for reformulating to extend patent life. But would people want the alternate day injections - it's easy to remember to take it daily but when its alternate days becomes complicated and what happens if you miss a dose? We know there is mild tachyphylaxis (diminishing response) with all drugs i.e. your side effects improve - with Copaxone the chest tightness improves; how will this be affected....

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  4. Teva wil do what it can to delay any competitor if they have to do a trial it delays them by 3 years and also ensures the generic price is high as they have to recoupe the costs. The six months delay with the appeal netted then 2 billion dollars.

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