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
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.
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.