Comparison of Copaxone® and Synthon's therapeutically equivalent glatiramer acetate.

Glatiramer acetate is indicated for the treatment of patients with relapsing forms of multiple sclerosis (RMS). In 2016, an alternative to the originator product was approved in the EU through the hybrid procedure regulatory pathway. This paper reviews the scientifically rigorous and multifaceted program undertaken to demonstrate the equivalence of this glatiramer acetate follow-on product (GTR) and the reference product Copaxone®, which resulted in the EU approval of GTR 20 mg/mL and 40 mg/mL. Establishing therapeutic equivalence for non-biological complex drugs is not trivial and requires a complex and multidisciplinary effort. Ultimately, there is not a single test or study that establishes therapeutic equivalence of two heterogeneous products. Instead, it requires a good understanding of the synthesis process together with a full set of data that includes comparative physicochemical testing, nonclinical in vitro and in vivo studies, and a comparative clinical study to allow for a valid conclusion that two products are therapeutically equivalent. The detailed understanding of glatiramer's synthesis process and its impact on the characteristics of glatiramer, combined with the results of a scientifically rigorous and multifaceted physicochemical and biological characterization program, and the clinical data from the 794-patient Phase III GATE study, demonstrate that GTR and Copaxone are therapeutically equivalent. The data further demonstrate that Synthon's manufacturing process consistently yields drug substance of the same quality as Copaxone and that switching from Copaxone to GTR is safe and well-tolerated.

Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation.

Glatiramer acetate (GA) is widely prescribed for the treatment of relapsing-remitting multiple sclerosis, however, the mechanism of action is still not fully understood. We investigated the structural properties of GA and examined alterations to the drug upon injection into the subcutaneous space. First, a variety of biophysical characterization techniques were employed to characterize GA in solution. GA was found to exist as alpha helices in solution with a hydrodynamic radius of ~3 nm in size. To simulate GA behavior at the site of injection, GA was injected into a solution of 1.5 MDa hyaluronic acid (HA). Visible aggregates were observed immediately upon injection and subsequent testing indicated aggregation was driven by electrostatic interactions between the positively-charged GA and negatively-charged HA. In vivo testing confirmed GA formed spherical particles in the nano- to micrometer size range, suggesting this mechanism contributes to persistence at the injection site and in draining lymph nodes. The aggregates were found to associate with glycosaminoglycans, suggesting an electrostatic mechanism of induced aggregation like the simulated injection. These novel observations may help explain the complex immunomodulatory mechanisms of GA and adverse injection site reactions seen in patients.

Equivalence of glatiramer acetate products: challenges in assessing pharmaceutical equivalence and critical clinical performance attributes.

INTRODUCTION: This review discusses the challenges to characterize and evaluate the peptide based drug glatiramer acetate (GA) and its follow-on products used for treatment of multiple sclerosis patients. AREAS COVERED: GA is a highly complex mixture of peptides consisting of four amino acids. The various (physico)-chemical approaches and bioassays used for characterizing this complex drug product are described. It is not possible to link data from preclinical performance to outcomes observed in clinical trials as no critical attributes suitable for predicting the clinical performance in MS patients have been identified yet. The limited insight into the precise mechanism(s) of action of GA may explain why these critical clinical performance attributes still have not been identified. EXPERT OPINION: The complexity of GA and lack of understanding of critical clinical performance attributes leads to a number of issues to be resolved as they hamper industry and regulatory bodies in designing and evaluating follow-on/generic applications of GA. The following questions are waiting to be addressed: Preclinical characterization vs clinical outcome: what is the relation? What are possible biomarkers? How to choose the right patient group? What is the experience with existing follow-on versions? Is there a place for GA 'betters'? How to evaluate existing and draft new guidance documents and pharmacopoeial monographs?

Compositional differences between Copaxone and Glatopa are reflected in altered immunomodulation ex vivo in a mouse model.

Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration-approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7-11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.

Eficacia del tratamiento inmunomodulador con interferón-β o acetato de glatirámero en las uveítis asociadas a esclerosis múltiple / Efficacy of immunomodulatory therapy with interferon-β or glatiramer acetate on multiple sclerosis-associated uveitis

Objetivo: Analizar la eficacia del interferón-β o acetato de glatirámero en reducir los episodios de inflamación intraocular en pacientes con uveítis asociada a esclerosis múltiple. Método: Estudio no aleatorizado, retrospectivo de serie de casos de 13 pacientes con diagnóstico definitivo de esclerosis múltiple y uveítis (seguimiento mínimo, 12 meses). Todos los pacientes fueron tratados con terapia inmunomoduladora (interferón-β o acetato de glatirámero) para controlar el curso de la esclerosis múltiple. Los pacientes fueron comparados con ellos mismos antes de iniciar el tratamiento inmunomodulador para valorar la diferencia en los episodios de uveítis. Variable principal de medida: número de episodios de uveítis con/sin tratamiento inmunomodulador. Resultados: Los brotes de uveítis fueron bilaterales en 10 de 13 pacientes (77%). Once pacientes fueron clasificados como uveítis intermedias, 3 pacientes como vasculitis retiniana y un paciente como uveítis posterior. Los pacientes tuvieron una media de 4,15±3,1 episodios de uveítis (rango 1-10) a lo largo del seguimiento (148,6±84,3 meses). Los pacientes bajo tratamiento con interferón-β o acetato de glatirámero mostraron una reducción significativa de 0,36 episodios de inflamación intraocular al año (p = 0,02) comparados con ellos mismos antes de iniciar el tratamiento. Seis pacientes (46%) mostraron efectos secundarios leves asociados al tratamiento inmunomodulador (3 pacientes [23%] síndrome seudogripal; 3 pacientes [23%] rash cutáneo). Conclusiones: El interferón-β o acetato de glatirámero podrían ser efectivos en reducir los brotes de inflamación intraocular en pacientes con uveítis asociada a esclerosis múltiple, siendo bien tolerados por la mayoría de los pacientes (AU)

Aim: To analyse the role of interferon-β or glatiramer acetate in reducing the inflammatory episodes of intra-ocular inflammation in multiple sclerosis-associated uveitis. Method: A study was conducted on a non-randomised, retrospective case series of 13 patients with proven multiple sclerosis and uveitis (minimum follow-up, 12 months). All patients were given immunomodulatory treatment (interferon-β or glatiramer acetate) to control the course of the multiple sclerosis. Patients were compared to themselves before initiating the treatment, in order to assess the difference in uveitis episodes. The main outcome measurements were the number of uveitis episodes with/without immunomodulatory treatment. Results: Uveitis was bilateral in 10 (77%) out of 13 patients. Intermediate uveitis was observed in 11 patients, retinal vasculitis in 3 patients, and one patient was classified as a posterior uveitis. The patients had a mean of 4.15±3.1 episodes of uveitis (range 1-10) during the follow-up period (148.6±84.3 months). When compared to their pre-treatment status, patients on treatment with interferon-β or glatiramer acetate showed a significant decrease of 0.36 episodes of ocular inflammation per year (P =.02). Mild side effects related to immunomodulatory treatment were observed in 6 (46%) patients, 3 (23%) patients with a flu-like syndrome, and 3 (23%) patients with a skin rash. Conclusions: Interferon β or glatiramer acetate could be effective in reducing the uveitis episodes in patients with multiple sclerosis-associated uveitis, and was well tolerated in most patients (AU)

Glatiramer Acetate 40 mg/mL in Relapsing-Remitting Multiple Sclerosis: A Review.

Glatiramer acetate (Copaxone(®)) is a synthetic analogue of myelin basic protein, which is thought to be involved in the pathogenesis of multiple sclerosis (MS). The therapeutic effects of the drug in the treatment of MS are thought to be via immunomodulation and neuroprotection. Subcutaneous glatiramer acetate 20 mg/mL once daily is approved in several countries for the treatment of relapsing forms of MS. Recently, a high-concentration formulation of glatiramer acetate 40 mg/mL administered three times weekly was approved in the USA and several European countries in the same indication. This article reviews the efficacy and tolerability of the high-concentration regimen. In the randomized, phase III GALA study in patients with relapsing-remitting MS (RRMS), glatiramer acetate 40 mg/mL three times weekly reduced annualized relapse rates significantly more than placebo, and indirect comparisons indicate that the efficacy of the three-times-weekly regimen is similar to that of the 20 mg/mL once-daily regimen. Results of the randomized, phase IIIb GLACIER study in patients with RRMS demonstrated that the three-times-weekly regimen reduced the risk of injection-site reactions by 50 % and was associated with numerically greater patient convenience scores than the once-daily regimen. Thus, in the treatment of RRMS, glatiramer acetate 40 mg/mL three times weekly is effective and provides a better tolerated and possibly more convenient option than the once-daily regimen.