Author byline as per print journal: G Castañeda-Hernández, PhD; L Carbajal-Rodríguez, MD; M Cerón-Rodríguez, MD; Professor LC Correa-González, MD; A Esquivel-Aguilar, PhD; SJ Franco-Ornelas, MD; JE García Ortiz, PhD; CM Hernández-Guadarrama, MD; JI Navarrete-Martínez, MD; Y Santillán-Hernández, MD; E Terreros-Muñoz, MD

Submitted: 8 February 2019; Revised: 19 May 2019; Accepted: 20 May 2019; Published online first: 3 June 2019

Introduction

Orphan drugs are biological or chemical drugs used for the prevention, diagnosis or treatment of rare diseases affecting no more than five in every 10,000 inhabitants [1–3]. Biological drugs (BD) are more complex molecules than chemical drugs; therefore, they should be assessed using specialized technical criteria and regulatory frameworks [4].

In Mexico, non-originator biological drugs should be approved according to the recommendations of the World Health Organization (WHO) and other international guidelines [1, 5–7]. However, the Mexican regulatory criteria to approve non-originator biological drugs for orphan diseases are unclear or unknown.

Objectives

This paper reviews the available scientific evidence relating to the non-originator imiglucerase in Gaucher disease (GD) to establish whether there are biosimilars of imiglucerase as a therapeutic option. In addition, the regulatory setting of non-originator biological drugs for orphan diseases is assessed, based on the approval of non-originator imiglucerase in Mexico.

Literature review

A bibliographic search in PubMed was conducted to gather information about GD and evidence regarding biosimilar orphan drugs and the regulatory framework. The keywords were limited to English language as follows: [Biosimilar Orphan Drug; Biosimilar Rare Orphan Disease; Biosimilar Gaucher disease, Biosimilar Imiglucerase]. The papers were discussed face to face in several academic sessions or electronically.

Additional or systematic analyses were not carried out. This may be a limitation because the inclusion and exclusion criteria were not delimited (with the exception of the keywords) and because, historically, data related to orphan drugs is scarce particularly for biological orphan drugs, compared with non-biological drugs in non-orphan diseases. Therefore, if the search criteria had been restricted to evidence-based medicine (or other accepted methods), it would have picked up less information.

A total of 47 articles were registered in the database. Only two publications were specifically related to non-originator imiglucerase, and two were related to the regulation of biosimilars in orphan diseases [8, 9]. The most relevant reports based on the keywords are described below.

Gaucher disease: an overview

Gaucher disease (GD, OMIM, #230800, #230900, #231000) is a lysosomal storage disorder. It is characterized by the accumulation of glucosylceramide (glucocerebroside) and other glycosphingolipids in the phagocyte mononuclear system cells in the liver, spleen and bone marrow. It is a genetic disorder with autosomal recessive mutations in the gene for glucocerebrosidase (OMIM, *606463), causing reduced or no activity of the acid-β-glucosidase enzyme (glucocerebrosidase or glucosylceramidase). This enzyme therefore has impaired catalytic function and/or diminished stability [10], enabling the accumulation of glucocerebroside in the Gaucher cells and monocytes. In the long term, this leads to hypertrophy of the cellular lysosomal system that infiltrates bone tissue, bone marrow, spleen, liver, lungs and brain, causing cell damage and organ failure.

The clinical manifestations in the visceral tissue and the vascular endothelium depend on macrophage density in the affected organs [10, 11]. One of the visceral manifestations of GD is splenic growth (to 1,500–3,000 cc, compared with the average 50–200 cc in adults), which causes splenomegaly-associated pancytopenia. The clinical spectrum is heterogeneous and often occurs at an early age. GD-related thrombocytopenia, a reduction in the number of mature blood cells (≤ 90 × 10⁹ platelets/L), may be the result of hypersplenism, platelets splenic sequestration, infiltration, or medullary infarcts. Anaemia and leukopenia may coexist simultaneously or independently, and also depend on splenic growth. Anaemia may be secondary to hypersplenism, and, in the advanced disease, the result of medullary failure secondary to Gaucher cells infiltration or medullary infarcts. Hepatomegaly is a very common manifestation of GD, while cirrhosis and hepatic failure are rare. Bone disease is generally the most disabling aspect of GD. Patients frequently experience bone pain with some having bone crisis and more than 20% of cases having mobility disorders. Pathologic fractures or avascular necrosis in the femoral head may also occur [12].

Three clinical forms of GD have been described: a) type 1 (non-neuronopathic disease) which accounts for > 90% of cases; b) type 2 (acute neuronopathic); and c) type 3 (subacute neuronopathic). GD is caused by mutations in the gene for glucocerebrosidase, located in the 1q21 chromosome; it has 11 exons distributed along 7.6 kb. More than 350 pathogenic variants have been reported and approximately 80% of them are replacements of one single nucleotide. Three mutations prevail in Western populations: c.1226A>G (p.Asn409Ser, N370S allele), c.1448T>C (p.Leu483Pro, L4444P allele), and c.84dupG (84GG allele). Regarding phenotype-genotype correlation, it has been determined that the N370S allele predicts a non-neuronopathic phenotype (GD type 1), whereas the homozygous state for L444P allele predicts a neuronopathic phenotype (GD type 2 or 3). In some rare cases, mutations in the PSAP (Prosaposin) gene cause a saposin C (activator protein) deficit, which may cause GD [13–16].

GD has a low prevalence, affecting approximately one in every 75,000 people in Western populations [17], and is therefore considered a rare disorder [1, 2]. There is a higher prevalence in some small populations where the level of consanguinity is high. In Mexico, this phenomenon has not been observed due to the large and diverse interbred population, except in some remote geographical areas [15].

Treatment of Gaucher disease in Mexico: Cerezyme and Asbroder

Treatment of GD aims to restore the activity of the glucocerebrosidase enzyme. Without treatment, the natural course of GD in any of its clinical manifestations is extremely adverse. Patients experience frequent complications as the diseases progresses, with high morbidity and mortality rates and decreased quality of life [13].

The available scientific evidence relating to non-originator biological orphan drugs was assessed in order to establish whether biosimilars are a therapeutic alternative treatment for GD in Mexico. ERT with alglucerase (mannose-terminated, human placental acid β-glucosidase, Ceredase, Sanofi Genzyme, Cambridge, MA) was approved in 1991 by the US Food and Drug Administration (FDA). The modified form of the acid-β-glucosidase enzyme, imiglucerase (Cerezyme, Sanofi Genzyme, Cambridge, MA), is produced by recombinant DNA technology in cultures of Chinese hamster ovary cells, and has been available since 1994 [18]. Cerezyme is recommended in Mexico for all patients with type 1 and type 3 GD [19]. Even though it is not curative, there is evidence supporting its safety and efficacy. It is proven to significantly diminish the haematological and visceral manifestations of GD, reduce bone marrow infiltration and improve skeleton quality as well as the quality of life of patients [20]. Reported benefits include restoration of haemoglobin concentration to normal levels or nearly normal levels within six to 12 months achieving a sustained response over five years, normalization of platelet count, reduction in hepatomegaly in 30% to 40% of cases, and reduction in splenomegaly in 50% to 60% of cases. In patients with bone pain or bone crisis, 52% had no pain after two years and 94% did not report further crisis [21].

Choi et al. conducted a switch-over clinical trial in 2015, ‘A phase 2 multi-center, open-label, switch-over trial to evaluate the safety and efficacy of Abcertin in patients with type I Gaucher disease’, to evaluate the efficacy and safety of Abcertin (ISU Abxis, Seoul, Korea) in five subjects with type 1 GD who were previously treated with imiglucerase [22]. Through indirect comparison, the results showed that the efficacy and safety of Abcertin was similar to that of the imiglucerase of reference.

Later on, the authors stated in an erratum that the product should not be regarded as a biosimilar (of imiglucerase), as defined by WHO [22–24]. In a second study conducted in 2017, ‘A multicenter, open-label, phase III study of Abcertin in Gaucher disease’, Lee BH et al. assessed the efficacy and safety of Abcertin in seven Egyptian patients with treatment-naïve type 1 GD. The results demonstrated the efficacy and safety of Abcertin in these patients [25]. However, the authors disclaim Abcertin as ‘another form of imiglucerase’, but not as a biosimilar according to the WHO definition [23].

Regulation of biological treatment options in Mexico

Asbroder is a new option for treating GD, however, it cannot be defined as a biosimilar of Cerezyme because it does not meet the WHO definition of a biosimilar. The regulatory setting in Mexico is complex, and the criteria to approve this non-originator imiglucerase for the treatment of GD are unclear. Mexican legislation of biological drugs was first discussed in Congress in 2007, and in 2009 a legislative procedure took place and reformed Mexican health laws. Following this, Article 222 Bis was enacted and outlined the general criteria that biological drugs including biosimilars must meet before reaching the market [26].

Regulation of biological and biosimilar drugs
In Mexico, the national health authority registers approved drugs. Both non-originator generic and biological drugs must meet legislation NOM-177-SSA1-2013 [27] ruled by Article 222 Bis in the Mexican General Health Law [28] (NOM-257-SSA1-2014 [29], and NOM-177-SSA1-2013, among others). Biological drugs must also be reviewed by two expert committees in the sanitary authority called Committee of New Molecules (Comité de Moléculas Nuevas) and Sub-committee of Biotechnological Drugs (Subcomité de Biotecnológicos).

Mexican law determines the requirements to validate innovative biologicals and biosimilars according to their characteristics and physiochemical complexity. Biosimilar drugs are not innovative according to legal definitions and, although advanced biotechnology allows adequate characterization of biomolecules, it is not always possible for a biosimilar drug to be identical to the originator drug (the ‘similar, but not identical’ paradigm) [5]. This is due to micro-heterogeneities in the raw materials and manufacturing processes. Manufacturers of biosimilar drugs must provide evidence from biosimilarity trials to prove that they meet quality, efficacy and safety criteria demonstrating their similarity to the originator biological drug [30–32]. It is noteworthy that the terms biosimilar and biocomparable are synonyms in Mexico, however, the correct legal nomenclature for non-originator biological drugs is ‘biocomparable’ to avoid any phonetic confusion that could be associated with a local generic drug brand.

The Mexican Official Norm NOM-257-SSA1-2014 (‘About biotechnological drugs’) specifies the requirements for evaluating technical and scientific information when registering a biological drug, as well as the criteria that the Mexican Health Ministry must follow to legalize the drug, general specifications for manufacturing, and the requirements that a biological drug must meet in order to be recognized as a reference biological drug. However, it is not specified in these laws that they apply to orphan drugs.

Non-originator biological orphan drugs
In Mexico, orphan drugs are not officially registered in the guidelines like other drugs are; instead, they are granted official recognition as an orphan drug. However, biological and biosimilar drugs for orphan diseases are not excluded from the aforementioned laws or regulations. This results in a complex situation because solid scientific evidence is not considered when demonstrating that non-originator drugs for orphan diseases have the same quality, safety and efficacy as the originator drug, and the health authority allows the import and trading of orphan drugs. This explains why the orphan biological drug Cerezyme for the treatment of GD did not undergo the same regulatory procedures as other drugs available in Mexico.

Since the Cerezyme patent expired, new products have been approved for the treatment of GD without an updated regulatory framework. In October 2015, an official communication of orphan drug recognition in Mexico authorized the commercialization of Asbroder, a presumed biosimilar drug of Cerezyme that shares the same international non-proprietary name, imiglucerase. Asbroder was the first of its kind to be approved in Mexico [33, 34]. Under the assumption of improving access for vulnerable patients, Asbroder did not need to apply to obtain a registry number (in Clave de Cuadro Básico y de Catálogo de Insumos del Sector Salud) to supply a health institution. Having the same international name implies recognition of biosimilarity in terms of quality, safety and efficacy. However, there is not sufficient analytic, preclinical and clinical trials evidence demonstrating such characteristics for Asbroder compared with Cerezyme. Therefore, the lack of standardized legislation for biosimilar treatments of rare diseases has a clinical impact on patients with GD [35].

The authors of the Korean study described above define Abcertin as ‘another form of imiglucerase’ [22]. The phrase ‘another form’ does not exist in any accepted international guidelines and therefore may confuse patients, physicians and health authorities. The drug contained in Abcertin should not be named ‘imiglucerase’; rather it should be identified with a different nomenclature, as is the case with velaglucerase and taliglucerase, where taliglucerase is identified as ‘another form’ of velaglucerase with differences in the chemical structure. This situation demonstrates the complexities surrounding biosimilar treatments for orphan diseases. There are significant legal gaps in the quality of the scientific evidence required for their approval and no source specifies the requirements a biosimilar drug must meet to obtain an official communication of recognition as an orphan drug. Consequently, the number and quality of tests required for orphan biosimilar approval are at the discretion of the health authority.

With this in mind, we must consider the issues that health authorities encounter when considering orphan biosimilar drugs. In Mexico, one of them is that scientific evidence relating to orphan products for rare diseases like GD do not have the endorsement of the health authority committee of experts, as Mexican legislation does not consider orphan diseases in its approval protocols. This means that the biosimilarity of a product is questionable when compared with the originator product. Likewise, the specific physicochemical characterization tests of orphan products, like imiglucerase, are not included in the Mexican Pharmacopoeia or in any other official document. This means that when the biosimilar manufacturer carries out in-house validations of the analytical methods and considers its specifications, there is no baseline scheme that underpins the comparisons. Thus, orphan drugs are not considered in the definitions of innovative and biosimilar drugs.

Proposed updates to regulation
In 2016, the Mexican health authority announced the establishment of a specialized group for orphan diseases and suggested that protocols on orphan drugs need to be updated in order to meet current scientific criteria [36].

In some circumstances, healthcare professionals may make the decision to switch without notifying the patient via informed consent; thus, the patients’ constitutional right to health protection is at risk [37]. Furthermore, pharmacovigilance – which requires adequate traceability systems – would be compromised. If two or more drugs share the same registry number to supply a health institution, it is impossible to know which drug is being administered. This could lead to a non-medical switch at the time of infusion without the physician or patient’s knowledge.

In light of these concerns surrounding orphan biosimilars, Asbroder must be thoroughly evaluated and given a new code in the Mexican List of Medications because it is not an interchangeable imiglucerase with Cerezyme. There is comprehensive data on the quality, efficacy and clinical safety of Cerezyme, but not for Asbroder; equivalent efficacy and safety following treatment switching to Asbroder have not been proven sufficiently.

Conclusion

Based on the literature, there are no biosimilars of imiglucerase for the treatment of GD. Asbroder is not a biosimilar of Cerezyme because it does not meet WHO’s definition or international guidelines. Further studies are required to show the efficacy and safety of Asbroder.

Position statement
Grupo de Especialistas Médicos en enfermedad de Gaucher expresses its position regarding biosimilar orphan drugs for the treatment of orphan diseases – using the case with Asbroder – as follows:

• Biological drugs are complex, and their clinical outcomes cannot be extrapolated to biosimilar drugs when clinical trial data designed to demonstrate therapeutic equivalence are lacking.
• For approval, biosimilar drugs need a different set of regulations from generics. They also need to provide evidence of quality, efficacy and safety equivalence versus the originator drug by means of proper analytical, preclinical and clinical trials. Biosimilar drugs are not interchangeable if efficacy and safety are not demonstrated.
• In Mexico, there are legislations for biological drugs, but they do not specifically include the requirements for biosimilar drugs targeted at orphan diseases.
• If therapeutic equivalence, efficacy and safety have not been demonstrated, indiscriminately switching to a biosimilar drug from an originator product represents a high risk for patients.
• If patients with GD are stable with an originator drug, they should not be automatically switched to a biosimilar because that is not ethically acceptable. It puts the patient at risk and there is no evidence supporting switching, or evaluation of the product’s long-term safety.
• Asbroder is a non-interchangeable biological drug and results cannot be extrapolated because there is not enough evidence available about its quality, efficacy and safety, compared to the originator drug. Thus, these biological products should not share the same naming and registration code to supply health institutions.
• It should be noted that the authors of this review are not against the use of biosimilar drugs, as long as they meet the requirements of WHO Guidelines, Mexican Health General Law (DOF 12-07-2018) and the current Mexican legislation.

Acknowledgments

We thank Vesalio Difusión Médica for the editorial support.

Funding

We acknowledge Sanofi Genzyme for supporting only the medical writing and paying the journal fees.

Competing interests: The authors declare no conflict of interest. Sanofi Genzyme only helped paying for the translation of the manuscript.

Provenance and peer review: Not commissioned, externally peer reviewed.

Authors

Gilberto Castañeda Hernández, PhD in Pharmaceutical Applications
National Researcher Level III, National Research System, Fellow of Academia Mexicana de Ciencias; Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, #2508 Avenue Instituto Politécnico Nacional, Colonia San Pedro Zacatenco, CP 07360, Ciudad de México, Mexico

Grupo de Especialistas Médicos en enfermedad de Gaucher (Group of Medical Specialists on Gaucher disease)

Luis Carbajal-Rodríguez, MD
Paediatrician, Consejo Mexicano de Certificación en Pediatría AC, certificate number 2029, Mexico City, Mexico

Magdalena Cerón-Rodríguez, MD
Paediatrician, Internist, Consejo Mexicano de Certificación en Pediatría AC, certificate number 4525, Mexico City, Mexico

Lourdes Cecilia Correa-González, MD
Professor of Clinical Research Sciences, Haematologist, Paediatrician and Oncologist, certificate number 105 from Consejo Nacional de Oncología, certificate number 014-2016 from Consejo Mexicano de Hematología, San Luis Potosí, SLP, Mexico

Abdieel Esquivel-Aguilar, PhD
Pharmacology, certificate number 0877917 from Centro de Investigación y de Estudios Avanzados in Instituto Politécnico Nacional, Mexico City, Mexico

Sergio Joaquín Franco-Ornelas, MD
Consejo Mexicano de Certificación en Pediatría, certificate number 5500, Mexico City, Mexico

José Elías García Ortiz, PhD
Human Genetics, certificate number 234, Consejo Mexicano de Genética AC, National Researcher Level II, National Research System-CONACyT, Guadalajara, Jalisco, Mexico

César Martín Hernández-Guadarrama, MD
Paediatrician, Haematologist, Consejo Mexicano de Hematología R-2018, Consejo Mexicano de Pediatría, certificate number 5288, Guadalajara, Jalisco, Mexico

Juana Inés Navarrete-Martínez, MD
Specialist on Medical Genetics, certified by Consejo Mexicano de Genética No.15, Mexico City, Mexico

Yuritzi Santillán-Hernández, MD
Specialist on Medical Genetics, certificate number 137, Consejo Mexicano de Genética AC Medical Genetics, Centro Médico Nacional ‘20 de Noviembre’, ISSSTE, Mexico City, Mexico

Eduardo Terreros-Muñoz, MD
Haematologist, certified by Consejo Mexicano de Hematología, Fellow of Agrupación Mexicana para el Estudio de la Hematología AC de CV, Mexico City, Mexico

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