Unsatisfactory quality of E. coli asparaginase biogenerics in India: Implications for clinical outcomes in acute lymphoblastic leukaemia

Abstract

Background The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli‐derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low‐middle‐income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. Procedure Seven biogeneric EcASNases (P1–P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2/dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug‐related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). Results In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high‐risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch‐to‐batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. Conclusions Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high‐quality asparaginases remains an unmet therapeutic need.

Precursor B‐cell acute lymphoblastic leukaemia—a global view

“…Many of these treatments are possible in India due to the availability of generics, and biosimilar preparations of drugs like L‐asparaginase (L‐ASAP) and rituximab. However, challenges remain 30,31 …”

“…However, challenges remain. 30,31 Our institution is a not-for-profit trust-based comprehensive cancer centre located in eastern India, and we are a regional referral institution. Referral pathways for cancer care in most of India are a work-in-progress, and are currently based on geographical access, payment patterns, and treatment experience and reputation of the centres.…”

Pharmacological and clinical monitoring in children with acute lymphoblastic leukemia treated with a biogeneric PEG‐l‐asparaginase product

“…ASP biogenerics have been also used to face occasional shortages occurring for the original product in countries other than LMIC. 6,7 However, some recent reports have shown relevant pharmacological differences between these products and the reference products. As an example, Zenatti et al have recently reported insufficient SAA levels in a cohort of patients treated with a biogeneric ASP, produced by a Chinese company and marketed in Brazil, reportedly because of a high protein contamination of the product.…”

“…8 Similar evidence has been reported by Sidhu et al and Sankaran et al when describing drug activity and biological features of different ASP biogenerics, manufactured in India, reporting inadequacy of those products in terms of protein's purity and identity, chemical quality of the formulation, and activity levels. 6,7 In this report, we describe the pharmacological and clinical effects associated with the use of a PEG-ASP biogeneric product, manufactured in India and administered in a limited cohort of patients during the induction phase of an AIEOP-BFM ALL backbone-based protocol.…”

Comment on: Unsatisfactory quality of E. coli asparaginase biogenerics in India: Implications for clinical outcomes in acute lymphoblastic leukaemia

“…3 In the present study, Sidhu et al showed that none of the seven biogeneric formulations of native asparaginase marketed in India met the minimum manufacturing quality standards required for these products. 4 In a similar manner, Sankaran et al analyzed nine generic formulations of L-asparaginase. They observed that none of the nine Indian generic formulations tested were able to consistently achieve a threshold of 100 IU/L.…”