The regulatory guidelines for biosimilars’ development consider the clinical comparability as confirmatory and the last step. Their recommendation is a head to-head comparison in a representative and sensitive subject population [5-7].

A proposed rituximab biosimilar (RTXM83) to the European Union (EU)-authorized originator (MabThera) was developed by mAbxience Research. A prospective, multicentre, double-blind, randomized clinical study (RTXM83-AC-01-11) was conducted to confirm comparable clinical performance (efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), safety and immunogenicity) of RTXM83 versus MabThera (NCT02268045), both in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as first-line treatment in Diffuse Large B Cell Lymphoma (DLBCL). Similar behaviour was anticipated in the clinical setting because the molecule has been shown to be structurally and functionally highly similar to the reference biological [5].

Rituximab is a chimeric anti-CD20 monoclonal antibody approved for the treatment of several types of non-Hodgkin’s lymphoma (NHL) and autoimmune diseases [8]. For these indications, a homogeneous population of DLBCL patients was chosen, as a sensitive indication that exhibits good clinical responses to rituximab [9, 10]. In this NHL subtype, rituximab is considered a standard of care for first-line treatment [9,11].

In total, 272 patients from 12 countries, <65 years of age and with a good prognosis, were randomized (1:1) to receive six cycles of either RTXM83 or MabThera (136 patients per treatment arm). All patients received at least one dose of the study treatment.

The primary efficacy endpoint was to compare the overall response rate (ORR) in each treatment arm after study treatment (cycle 6 or within 30 days after last administration of study treatment). This is considered a sensitive and appropriate indicator of activity by both European Medicines Agency (EMA) and US Food and Drug Administration (FDA) guidance [6, 7] for a biosimilar antibody such as rituximab, due to its treatment effect.

PK and PD profile, event-free survival (EFS), safety and immunogenicity profiles were assessed as secondary study endpoints.

Baseline demographic and clinical characteristics were comparable between treatment arms. The study met its primary endpoint by confirming the non-inferior efficacy (in terms of ORR) of RTXM83 to MabThera in the first-line treatment of DLBCL [12], with the lower boundary of the confidence interval (CI) of the treatment effect difference (-8.77%) not exceeding -13%. EFS was achieved in both treatment arms and was comparable. In addition, the Hazard Ratio (HR) was nearly 1 which indicates that the rate of events occurring in the biosimilar arm and the MabThera arm were nearly the same [12].

For the secondary endpoints, the results of the PK/PD assessment demonstrated a similar PK/PD profile for RTXM83 and MabThera [13]. The overall safety profile of RTXM83 was consistent with the known safety profile of rituximab plus CHOP in DLBCL [8], with haematological disorders, infections and infusion-related reactions as the most common reactions. Both treatments showed a comparable safety profile, with no differences in terms of the nature, frequency and severity of adverse events and no new safety signals identified in the study [12].

The rates of immunogenicity observed in the study [12, 13], were low (<4%) and similar in both treatment arms and raised no concern around the efficacy or safety compared to the MabThera safety profile [8].

Candelaria et al. conclude that RTXM83 has demonstrated biological activity comparable to MabThera and is expected to enhance treatment options, improving patient access [12].

Conflict of interest
The authors of the research paper [12] reported conflict of interest, including being an employee of mAbxience Research. They also reported that this work was supported by mAbxience Research. For full details of the authors’ conflict of interest, see the research paper [12].

Abstracted by Luis Pérez Díaz, Medical Advisor, 28 C/Manuel Pombo Angulo, 4th Floor. ES-28050 Madrid, Spain.

Editor’s comment
Readers interested to learn more about rituximab biosimilars are invited to visit www.gabi-journal.net to view the following manuscripts published in GaBI Journal:

Biosimilar rituximab in biological naïve rheumatoid arthritis patients

Phase I studies of infliximab and rituximab biosimilars demonstrate pharmacokinetic similarity

GaBI Journal is indexed in Embase, Scopus, Emerging Sources Citation Index and more.

Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal – please send us your submission here.

Related articles
PK and PD comparison between rituximab biosimilar RTXM83 and rituximab in diffuse large B-cell lymphoma patients

Biosimilars of rituximab

References
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