Biosimilars: New or Déjà Vu?

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By Jonathan Kay

Arthritis & Rheumatology

Volume 68, Issue 5, pages 1049–1052, May 2016

 

Since the US Food and Drug Administration (FDA) first approved the anti–tumor necrosis factor (anti-TNF) monoclonal antibody infliximab in 1998 to treat patients with inflammatory bowel disease, targeted biologic therapies have revolutionized the treatment of inflammatory diseases. However, their high cost has limited access to these very effective agents for many patients. Thus, biosimilar agents are being developed so that these biopharmaceuticals can be made available at significantly lower prices. CT-P13, a biosimilar infliximab developed in South Korea by Celltrion, was the first biosimilar therapeutic monoclonal antibody approved by a regulatory agency, and it was approved by the US FDA on April 5, 2016. In this issue of Arthritis & Rheumatology, Kim and colleagues report on the use of CT-P13 in South Korea during the first 16 months after its introduction in November 2012 [1].

 

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Biosimilar Drugs for RA Studied in Multiple Trials

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The Rheumatologist

August 17, 2015 • By

Etanercept Biosimilars

A number of Phase 3 trials are ongoing for etanercept biosimilars.1One evaluation identified three trials in rheumatoid arthritis (RA) patients and one in psoriasis patients. The psoriatic arthritis trial evaluated PASI as a primary endpoint and the following secondary endpoints: PASI50, PASI75, PASI90, PASI score, laboratory values, ECG, adverse events (AEs), injection site reactions and immunogenicity. The RA trials are evaluating ACR20 as the primary endpoint. Secondary endpoints include ACR50, ACR70, DAS28, AEs, serious AEs, safety and immunogenicity.

Copies. What’s a biologic copy?

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A copy is a biological agent that has been launched to the market claiming that has the same properties, in terms of efficacy and safety than those of the biological agent of reference. Nevertheless, the big difference with biosimilars, is that in no case have been developed with the standards of quality required for biosimilars. This is the main reason why these ‘copies’ have not been approved by the most important regulative agencies, as the EMA (European Union) and the FDA (USA); and therefore they will never be commercialized in these countries. Usually, they are produced in India or China and have managed to be commercialized in some countries. But at the present is very difficult for me to know exactly in which countries are available.

Biosimilars. Definition. Advantages…?

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Though the definition is not comparable, we could say that a biosimilar is the ‘generic’ of the biologic of reference. Nevertheless in no case the ‘generic’ term must be used to refer to a biological agent. A generic drug is a chemical compound with an identical formulation that the original formula. The only difference is the excipient that shapes the product (see generics in another part of this blog). A biosimilar, is an extremely complex protein, of great molecular size, which has efficacy and safety similar to the product of reference. As an example, Remicade (Infliximab) has already on the European market and in other countries a biosimilar, with two different trade names, Remsima and Inflectra. To approve a biosimilar is required to carry out pre-clinical tests and face to face clinical trials against the product of reference. Pre-clinical tests and efficacy and safety must be comparable to the reference product. Biosimilars only can be launched once the product of reference has lost its patent, which should occur ten years or more, depending on the Country, after being in the pharmaceutical market. The main advantage of biosimilars is the price. Is estimated that they will be between 30 to 50% cheaper than the original product. In the next 10-15 years, the hypothetical success of biosimilars will depend on several factors. Among them, the country policy in heath care can be very relevant. In Spain, for example, a country with a strong Public Health Care System, in which, the State pays biologics through the citizens taxes, the government might decide buying only biosimilars instead the reference product. Another possibility is that the Pharmaceutical Company that produces the original product decides to reduce the price to the levels of biosimilars. Nonetheless, we’re at the beginning of a new era, with only one biosimilar approved, and to speculate about what will happen with biosimilars might be confusing. At the present, we still have more questions than answers.

Definition of Biosimilar by the EMA (European Medicines Agency): A biosimilar is a medicinal product that contains a version of the active substance of an already authorized original biological medicinal product (reference medicinal product). A biosimilar demonstrates similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise

Definition of Biosimilar by the FDA (USA): 

A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.

¿Qué es una Copia de un Biológico?

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Una copia es un agente biológico que ha sido lanzado al mercado aduciendo que tiene las mismas propiedades tanto en términos de eficacia como de seguridad que las del agente biológico de referencia. No obstante, la gran diferencia con los biosimilares, es que en ningún caso se han desarrollado con los estándares de calidad que se les pide a los biosimilares. Por ello, estas ‘copias’ no han sido aprobadas por las agencias regulatorias más importantes, como la EMA ( Unión Europea) y la FDA (Estados Unidos), y por tanto nunca serán comercializados en estos países. Normalmente son producidos en India y en China y han llegado a ser comercializados en algún país Latino-Americano, del área del Caribe, aunque en el momento de escribir estas líneas, desconozco si siguen en esos mercados o han sido retirados. Sí me consta, sin embargo, que ni en Argentina, Chile, ni Brasil, entre los países de America del Sur, ni en México, como país representativo del área geográfica de América del Norte, han llegado a ver la luz. No obstante, estaría encantado, si alguno de los lectores de este blog me pudiera rectificar o ratificar estos aspectos, ya que es a veces difícil conocer la situación real de estos fármacos.

¿Qué es un Biosimilar ¿Aporta ventajas?

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Aunque la definición no es equiparable, se podría decir que el biosimilar es el ‘genérico’ del agente biológico de referencia. Sin embargo en ningún caso debe emplearse el término ‘genérico’ para referirse a un agente biológico. Un fármaco genérico es una formulación química, idéntica a la de la fórmula original, con la única diferencia del excipiente que conforma el producto (ver genéricos en otros apartados de este blog). Un biosimilar, es una proteína sumamente compleja, de gran tamaño molecular (ver ilustración) que tiene una eficacia similar al producto de Sin títuloreferencia. Por ejemplo, el Remicade® (Infliximab) tiene ya en el mercado europeo y en otros países un biosimilar de Infliximab, con dos nombres  comerciales diferentes: Remsima® e Inflectra®. Su diseño y construcción es mucho más compleja que la de un genérico, y al margen de exigirsele pruebas preclínicas exhaustivas, se le exige realizar ensayos clínicos comparándolo con el biológico original, para demostrar que su eficacia y seguridad es la misma. Sin embargo, en ningún modo la exigencia en estos ensayos clínicos es tan grande como la que se le exigió a Remicade en su día. Por poner un ejemplo: con este biosimilar solo se han hecho estudios clínicos en la Espondilitis Anquilosante (EA) y en la Artritis Reumatoide (AR), los cuales demostraron ser prácticamente idénticos en eficacia en estas enfermedades. Sin embargo, no se han hecho estudios (ahora se está haciendo uno) en la enfermedad intestinal inflamatoria (Crohn), para lo cual Remicade también tiene su aprobación de uso. No obstante, la EMA (Agencia Europea del medicamento) ha aprobado la ‘extrapolación’, esto es: ha considerado que si el fármaco es prácticamente idéntico al original y ha demostrado ser igual de eficaz en la AR y en la EA, no hay motivos para pensar que no lo sea en el Crohn. No obstante, no todo el mundo está de acuerdo con esta asunción, y de hecho la Agencia de Medicamentos Canadiense no lo ha aprobado, de momento, para la enfermedad de Crohn.

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