Biosimilar Monoclonal Antibodies in Latin America

*Paola Karp, Matías Gatto, María Victoria Batto, Sol Ferrero and Gustavo Helguera*

## **Abstract**

In the last decade, the expiration of patents protecting therapeutic monoclonal antibodies opened an opportunity for the development and approval of biosimilar versions of these drugs. The complexity of these biologic molecules required the imposition of strict regulations to establish robust comparability with the antibody of reference in physicochemical, analytical, biological and, when deemed necessary, clinical data. Accordingly, this period coincides with the updating of the requirements and guidelines for the manufacture and approval of biologics in Latin American countries by their respective regulatory agencies. Although the term "biosimilar" does not appear in the official regulatory provisions in most of the countries, it is of general use in Latin America, and several biosimilars of therapeutic monoclonal antibodies were approved based on comparative quality, nonclinical and clinical data that demonstrate similarity to a licensed biological reference registered before in a Regulatory Health Authority of reference. Here, we provide an overview of how the complexities of therapeutic monoclonal antibodies shaped the regulatory landscape of similar biologics, the current status of biosimilar monoclonal antibodies in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, México, Paraguay, Perú and Uruguay and their potential to reduce the cost of antibody therapies in this region.

**Keywords:** monoclonal antibody, biosimilar, biologics, Latin America, Argentina, Brazil, Chile, Colombia, México, Perú

### **1. Introduction**

### **1.1 The evolution of monoclonal antibodies to biologic medicines**

Antibodies, also known as immunoglobulins, are complex glycoproteins produced by B-cells against foreign substances as part of the adaptive immune response [1, 2]. The invention of the hybridoma technology in 1975 by Köhler and Milstein allowed the production of monoclonal antibodies with a desired specificity from a unique clone of B cells [3]. In contrast to polyclonal antibodies, monoclonal antibodies are homogeneous, monospecific, and could be produced in unlimited quantities in the laboratory. Since they can be directed against almost any molecular epitope, monoclonal antibodies were early adopted as a diagnostic tool, but took more than a decade until the approval of Muromonab-CD3 (Orthoclone Okt3®), which is the first monoclonal antibody developed with the hybridoma technology commercialized for therapeutic use [4]. However, since antibodies from hybridoma technology

have only murine sequences, in human patients they exhibited limited effector function [5], were immunogenic inducing anti-mouse antibodies, and had a significantly reduced half-life [6]. Therefore, it was not until the development of recombinant monoclonal antibodies in the 1980s and 1990s that a new era of biologic therapy began, with the chimerical [7], humanized [8] and fully human antibodies [9]. Each step involved the gradual replacement of murine segments of the antibody sequence by the corresponding human sequence: in chimeric antibodies the constant region was replaced, and in humanized antibodies, the framework flanking the complementarity-determining regions and the constant region were replaced, and in human monoclonal antibodies the whole sequence is human. Further engineering allowed their customization, creating variants in valence, size, effector functions and with the conjugation of compounds for delivery to targeted cell types such as cancer.

### **1.2 The emergence of biosimilar antibodies and Latin America**

In the last twenty years, therapeutic monoclonal antibodies have been increasingly and consistently approved and by 2021 it is estimated that 106 monoclonal antibodies would have been approved in the United States or European Union for treatment of an expanding spectrum of diseases [10]. The emergence of nextgeneration therapeutic monoclonal antibodies in the last decade coincides with the expiration of the patents protecting the early recombinant monoclonal antibodies [11]. The approval in 2013 of the infliximab biosimilar Remsima® [12] opened an emerging field of competition all over the world, with the development of biologic copies that exhibit equivalent quality and efficacy compared to the original antibodies. It was also an opportunity for biopharmaceutical companies in Latin America to enter this market, encouraged also by their governments. However, monoclonal antibodies post-translational modifications include different degrees of glycosylation, disulphide bridge variants, or C/N terminal modifications that are dependent on the manufacturing process [13]. Because of this structural complexity, regulatory agencies in Latin America went through profound changes in their standards in order to update the criteria for evaluation and approval of antibody biosimilars, requiring comparability analysis in safety and efficacy. Today, their requirements usually include the provision of detailed physicochemical, pharmaceutical, and biological information regarding critical quality attributes of the active principle and the manufacturing process. In addition, the comparability also requires establishing if there are variations in the type of host cell to produce of the recombinant protein, the amino acid sequence, the secondary, tertiary, and quaternary structure, interactions, post-translational modifications, the formulation, as well as impurities related to the process or storage. The challenge for their approval by regulatory agencies is reshaping the accessibility of these expensive medicines in Latin America. Here we focus our analysis on biosimilars that have been characterized in their physicochemical properties and showed evidence of quality, efficacy and safety published in the scientific literature, and will not include products known as copies or intended copies whose sponsors have failed to present sufficient evidence of their equivalence to the product of reference.

### **1.3 Regulation of biosimilars in Latin America**

Aiming to meet the international standards for production and development of biologic medicines, since 2008, Latin American countries began joining the Pharmaceutical Inspection Co-operation Scheme (PIC/S) and today Argentina, Brazil and Mexico are members. This organization sets standards in the international development, implementation and maintenance of harmonized Good

### *Biosimilar Monoclonal Antibodies in Latin America DOI: http://dx.doi.org/10.5772/intechopen.101227*

Manufacturing Practices (GMP) and quality systems of inspectorates of medicinal products. Only these three countries in Latin America have developed a biotechnology industry that include private companies with the capacity to manufacture biologic medicines. Meanwhile, today most countries in Latin America have approved specific regulations for the registry of biologic medicines and of similar biotherapeutic products or biosimilars. The World Health Organization uses a definition for these medicines as "biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product" [14]. As expected, each country in Latin America has adopted its own regulatory framework for the registration and approval of biosimilars.

The registration of biosimilar medicines in Argentina is controlled by the National Administration of Drugs, Foods and Medical Devices (Administración Nacional de Medicamentos Alimentos y Tecnología Médica, ANMAT). In 2011 was published provision N° 7729/2011, that "approved the requirements and guidelines for the registration of medicinal specialties of biological origin whose qualitative-quantitative composition, therapeutic indication and proposed route of administration, have precedents in other medicinal specialties of biological origin authorized and registered before this Administration or another Regulatory Health Authority (medicine biological reference or comparator), of which there is evidence of effective commercialization and sufficient characterization of its risk-benefit profile" [15]. The term "biosimilar" is not used in any of the regulatory provisions of ANMAT approved to date [16], referring to these products as "similar biological medicines".

In Brazil, the National Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria, ANVISA) is the registry agency in charge of the approval of the biosimilars, which is regulated under the resolution RDC 55/2010 [17, 18]. Although ANVISA does not use the term "biosimilar" in its resolution, its definition is merged with the term "biological product", which is defined as the non-new or known biological medicine that contains a molecule with known biological activity, already registered in Brazil and that has gone through all manufacturing steps (formulation, filling, lyophilization, labelling, packaging, storage, quality control and release of the batch of biological product for use) [17]. The approval of these biological products will require comparability studies with a biological comparator with regard to non-clinical and clinical parameters based on quality, efficacy and safety, in order to establish that there are no detectable differences in terms of quality, efficacy and safety between the products. The biological drug of reference or innovator receives the name of "new biological medicine", and the product of reference "comparator biological product" is a biological product that has already been registered with ANVISA on the basis of a complete dossier and has already been marketed in the country.

The National Medicines Agency (Agencia Nacional de Medicamentos, ANAMED) is the regulatory agency in Chile that regulates the technical standard for sanitary registration of biotechnological products derived from recombinant DNA techniques. In their regulatory technical norm for biologic medicines, the term biosimilar is defined as "the biotechnological medicine that has been shown to be comparable in quality, safety and efficacy to the reference biotechnological product, based on its exhaustive characterization through comparability studies under equal conditions, consisting of quality studies and non-clinical and clinical studies, all of them comparative" [19, 20].

The regulatory agency responsible for the approval of biologic medicines in Colombia is the National Drug and Food Surveillance Institute (Instituto Nacional de Vigilancia de Medicamentos y Alimentos, INVIMA). In 2014, the Decree N° 1782 [21] that describes the registration pathway for biosimilars in that country was published. Even though the directive does not use the term "biosimilar", it refers to them as "similar biotherapeutic products" and established a specific regulatory system for their registry. This application requires a series of tests comparing the

attributes of quality, safety and efficacy between the biosimilar and the biologic reference medicine to demonstrate that the drug under evaluation is highly similar to the reference drug [21].

The regulation of biologic medicines in Ecuador is overseen by the Regulatory, Control and Surveillance National Agency (Agencia Nacional de Regulación, Control y Vigilancia Sanitaria, ARCSA). The Health Ministry approved in 2019 the agreement 385 that regulates the commercialization of biological medicines for human use and consumption in Ecuador, as well as to establish the general procedure for obtaining the Sanitary Registry. In this directive, the biosimilars are defined as a biological medicinal product that has been shown by the comparability exercise to be similar in terms of quality, safety and efficacy to the reference biological medicinal product [22, 23].

Mexico is another country where the term "biosimilar" is not used in their regulatory norms for approval of biologic medicines. The Federal Commission for Sanitary Risks Protection (Comisión Federal para la Protección contra Riesgos Sanitarios, COFEPRIS) is the agency in Mexico responsible for regulating the approval, manufacture and commercialization of biologic medicines. The norm NOM-257-SSA1-2014 establishes the regulatory framework for biotechnological medicines and refer to "biocomparable biotechnological medicine", as the noninnovative biotechnological medicine that proves to be comparable in terms of safety, quality and efficacy of the reference biotechnological medicine through biocomparability studies [24, 25].

The registration of biological medicines in Paraguay is regulated by the National Directorate for Sanitary Surveillance (Dirección Nacional de Vigilancia Sanitaria, DINAVISA). The Decree N° 6611 approved in 2016 established the requirements for the approval of biologic medicines and includes the definition for similar biologic medications or biosimilars [26]. In this decree, biosimilars are defined as a biological medicine product that demonstrates similarity in terms of safety, quality, efficacy and immunogenicity to the reference biological medicinal product through the comparability exercise [26].

In Peru, the General Directorate of Pharmaceuticals, Devices and Drugs (Dirección General de Medicamentos, Insumos y Drogas, DIGEMID) is the agency in charge of the regulations and norms regarding approval and certification of biologic medicines. In 2016 the Supreme Decree N° 013-2016-SA that regulates the registration of biological products, which choose the path of similarity, or similar biologic products was approved [27]. In this norm, they are defined as the biological product, which in terms of quality, safety and efficacy, is similar to a biological reference product [27].

Most of the remaining countries in Latin America do not have dedicated agencies or specific norms that regulate the approval and surveillance of biosimilars, and therefore will not be included in this analysis [25].

### **2. Biosimilar monoclonal antibodies approved in Latin America**

Currently there are five therapeutic monoclonal antibodies registered in Latin America whose patents expired in recent years and have biosimilar versions commercialized in the region (**Figure 1**). Those are rituximab, trastuzumab, infliximab, adalimumab and bevacizumab, and only Argentina, Brazil and Colombia have at least one biosimilar version approved for each monoclonal antibody (**Figure 1**). With more than ten biosimilars approved, Argentina and Brazil are the countries in Latin America with more biosimilar monoclonal antibodies approved. Next are Colombia, Peru, Paraguay, Mexico and Chile, with 3 to 5 biosimilars of monoclonal antibodies, and the lowest adoption of biosimilars is in Ecuador, Bolivia and Uruguay *Biosimilar Monoclonal Antibodies in Latin America DOI: http://dx.doi.org/10.5772/intechopen.101227*

### **Figure 1.**

*Comparative plot of the number of biosimilars approved in Latin American countries.*

(**Table 1** and **Figure 1**). Recent reports indicate that in Brazil the prices in U.S. dollars of original biologics, including therapeutic monoclonal antibodies, have been declining significantly in the last decade. The emergence of competition by biosimilars, with their lower prices may strengthen this trend [28]. It is expected that the approval of more biosimilar monoclonal antibodies will increase the competition, decreasing the healthcare costs and expanding the accessibility of this class of drugs.

### **2.1 Rituximab**

Developed by Genentech in the United States, rituximab is marketed with the brand name Rituxan® (also known as MabThera®) and is currently commercialized by Roche. Rituximab is a murine/human chimeric monoclonal antibody with IgG1 / κ isotype directed against the CD20 antigen expressed by B cells used for the treatment of non-Hodgkin´s lymphoma (NHL), chronic lymphocytic leukaemia (CLL) [29], and rheumatoid arthritis [30]. Rituximab was approved by the FDA in 1997 for the treatment of B-cell Lymphomas and was the first chimeric recombinant monoclonal antibody approved against cancer. Several biosimilars of rituximab have been developed over the years, and by 2021 there are five different biosimilars of rituximab approved in Latin America, with nine different brand names commercialized in Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Paraguay, Peru and Uruguay (**Table 1**).

### *2.1.1 Ruxience® (Pfizer)*

PF-05280586 (Ruxience®) is a biosimilar of rituximab developed in the United States by Pfizer and commercialized in Brazil as Ruxience® by Wyeth Industria Farmaceutica. It is a monoclonal antibody used in the treatment of various types of cancer and immunological indications. In Brazil, PF-05280586 was approved with the same therapeutic indications approved for the reference rituximab.

Comparative biochemical and functional characterization were carried out to determine the level of physiochemical similarity, tryptic peptide maps were generated for both PF-05280586 and rituximab-EU and resolved by reverse-phase highperformance liquid chromatography Ryan [31]. This study proved that PF-05280586 has an identical primary amino acid sequence to rituximab. Additionally, it was demonstrated to be highly similar based on the comparison of physicochemical critical attributes, and non-clinical *in vitro* functional characteristics [31].


*# Reference Monoclonal Antibodies. Countries: Argentina (AR); Austria (AU); Bolivia (BO); Brazil (BR); Chile (CH); Colombia (CO); Ecuador (EC); Germany (GE); India (IN); Iran (IR); Mexico (ME); Paraguay (PA); Peru (PE); Russia (RU); South Korea (SK); Switzerland (SW); Uruguay (UR); and United States (US).*
