Sunday, 18 October 2015

Copaxone Generics on the way

Cohen J, Belova A, Selmaj K, Wolf C, Sormani MP, OberyƩ J, van den Tweel E, Mulder R, Koper N, Voortman G, Barkhof F; Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) Study Group. Equivalence of Generic Glatiramer Acetate in Multiple Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2015 Oct 12:1-9. doi: 10.1001/jamaneurol.2015.2154. [Epub ahead of print]

IMPORTANCE:The patents for the first approved treatments for relapsing-remitting multiple sclerosis are expiring, creating the opportunity to develop generic alternatives.
OBJECTIVE:To evaluate in the Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) study whether generic glatiramer acetate (hereafter generic drug) is equivalent to the originator brand glatiramer acetate (hereafter brand drug) product, as measured by imaging and clinical end points, safety, and tolerability.
DESIGN, SETTING, AND PARTICIPANTS:Randomized, multicenter, double-blind, active and placebo-controlled phase 3 trial. The setting included academic medical centers and clinical practices. Participants were patients with relapsing-remitting multiple sclerosis 18 to 55 years old with at least 1 relapse in the prior year and 1 to 15 gadolinium-enhancing brain magnetic resonance imaging lesions. They were randomized between December 7, 2011, and March 21, 2013. The last participant completed follow-up December 2, 2013.
INTERVENTIONS:Participants were randomized 4.3:4.3:1 to receive generic glatiramer acetate (20 mg), brand glatiramer acetate (20 mg), or placebo by daily subcutaneous injection for 9 months.
MAIN OUTCOMES AND MEASURES:The primary end point was the total number of gadolinium-enhancing lesions during months 7, 8, and 9. Additional end points included other magnetic resonance imaging parameters, annualized relapse rate, and Expanded Disability Status Scale score. Safety and tolerability were assessed by monitoring adverse events, injection site reactions, and laboratory test results.
RESULTS:In total, 794 participants were randomized and treated with generic drug (n = 353), brand drug (n = 357), or placebo (n = 84). The estimated mean numbers of gadolinium-enhancing lesions with generic drug and brand drug were lower than with placebo (ratio, 0.488; 95% CI, 0.365-0.651; P < .001), confirming study sensitivity. For gadolinium-enhancing lesions, the estimated ratio of generic drug to brand drug was 1.095 (95% CI, 0.883-1.360), which was within the predefined equivalence margin of 0.727 to 1.375. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the generic drug and brand drug groups.
CONCLUSIONS AND RELEVANCE:As treatment for relapsing-remitting multiple sclerosis, glatiramer acetate generic drug and brand drug had equivalent efficacy, safety, and tolerability.

So companies can still get away with placebo rather than have to do just non-inferiority (my drug is not worse than your drug) between the comparator. It tells us what the people on the ethics panels and importantly the regulators think about people with conditions....otherwise placebo control would be a no no. At least it was based on lesions and not relapses, but it says generics can work too.


CoI ProfG was on the data and safety monitoring board

One way that Teva has been saying that the GA me-too is different is to show it elicits a different gene profile

Towfic F, Funt JM, Fowler KD, Bakshi S, Blaugrund E, Artyomov MN, Hayden MR, Ladkani D, Schwartz R, Zeskind B.Comparing the biological impact of glatiramer acetate with the biological impact of a generic.PLoS One. 2014 Jan 8;9(1):e83757. doi: 10.1371/journal.pone.0083757.

So the next company is wise and shows that their me-too is not different.

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 Oct 16;10(10):e0140299. doi: 10.1371/journal.pone.0140299. eCollection 2015.


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.

So generic Glaterimer acetate is on the way, but what next
Rogstad S, Pang E, Sommers C, Hu M, Jiang X, Keire DA, Boyne MT 2nd.Modern analytics for synthetically derived complex drug substances: NMR, AFFF-MALS, and MS tests for glatiramer acetate. Anal Bioanal Chem. 2015 Oct 12. [Epub ahead of print]

Glatiramer acetate (GA) is a mixture of synthetic copolymers consisting of four amino acids (glutamic acid, lysine, alanine, and tyrosine) with a labeled molecular weight range of 5000 to 9000 Da. GA is marketed as Copaxone™ by Teva for the treatment of multiple sclerosis. Here, the agency has evaluated the structure and composition of GA and a commercially available comparator, Copolymer-1. Modern analytical technologies which can characterize these complex mixtures are desirable for analysis of their comparability and structural "sameness." In the studies herein, a molecular fingerprinting approach is taken using mass-accurate mass spectrometry (MS) analysis, nuclear magnetic resonance (NMR) (1D-1H-NMR, 1D-13C-NMR, and 2D NMR), and asymmetric field flow fractionation (AFFF) coupled with multi-angle light scattering (MALS) for an in-depth characterization of three lots of the marketplace drug and a formulated sample of the comparator. Statistical analyses were applied to the MS and AFFF-MALS data to assess these methods' ability to detect analytical differences in the mixtures. The combination of multiple orthogonal measurements by liquid chromatography coupled with MS (LC-MS), AFFF-MALS, and NMR on the same sample set was found to be fit for the intended purpose of distinguishing analytical differences between these complex mixtures of peptide chains.

However generics are on the way. Copaxone is making about $4 billion a year so others want a slice of the pie.

3 comments:

  1. J Cohen et al. have taken almost two years to publish the first study, I wonder why?

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  2. Abit cryptic NDG....what are your thoughts?

    I am guessing that as the legal battle of teva and Siphon and generics and the issue of when the patents expire. I think they are now gone and Siphon is on the way and they are free to market the drug so this is an advert. Maybe it is time for the regulators...ProfG knows but is gagged

    It synthon made announcment to stoxk market in April 2015 maybe it was submitted after this.

    There were the court cases too
    http://www.eplawpatentblog.com/eplaw/2015/06/uk-synthon-v-teva.html

    http://www.kwm.com/en/uk/knowledge/insights/patents-court-decision-on-synthons-challenge-to-copaxone-patents-20150622

    IIn the JAMA paper It says the "The study sponsor (Synthon BV) was responsible for the design and undertaking of the trial, the data analysis and interpretation, the writing of the manuscript, and the decision to submit the manuscript for publication".

    So if they were responsible for writing the manuscript why are they not first authors. I thought the issue of ghost writers was supposed to be transparent...I guess not yet.

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  3. Generic drugs are an excellent alternative to the exorbitant prices of medicines; okay, we know that a lot of money involved in the development of high technologies, especially in medicine, but we also know that there are as many shouldering with extremely high prices, especially when dealing with drugs with low efficacy ... Could a study to evaluate the possibility of using Cladribine and Glatiramer Acetate together? I read somewhere an evaluative study of alemtuzumab and Copaxone together ... I'll see if I can find the link of the publication...

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