Rituximab biosimilar RTXM83 versus reference rituximab in combination with CHOP as first-line treatment for diffuse large B-cell lymphoma: a randomized, double-blind study.

This multicenter, double-blind, randomized study compared the efficacy, pharmacokinetics (PKs)/pharmacodynamics (PDs), safety and immunogenicity profile of RTXM83 vs. reference rituximab (R-rituximab), both with CHOP, as first-line treatment of diffuse large B-cell lymphoma (DLBCL). A total of 272 patients <65 years of age, with good prognosis (136 per arm) were randomized (1:1) to receive six cycles of either RTXM83 or R-rituximab. The primary efficacy endpoint was achieved (overall response rate of 83.6% for RTXM83 and 82.9% for R-rituximab) with a difference 0.7% between arms (95%CI: [-8.77% to 10.17%]) fulfilling the predefined non-inferiority margin (-13%). Similar number of patients reported at least one adverse event (AE) (131 per arm) or one serious AE (47 with RTXM83 and 45 with R-rituximab). Anti-drug antibody development was comparable between the arms. PK/PD secondary endpoint results support similarity between the compounds. RTXM83 exhibits non-inferior efficacy and similar safety/immunogenicity to R-rituximab, being an accessible alternative for the treatment of patients with previously untreated DLBCL.

Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83™, a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach.

PURPOSE: The main objective was to quantify any potential differences in pharmacokinetic (PK) parameters (AUC and Cmax) between RTXM83, a proposed rituximab biosimilar, and its reference product, using a population PK model approach. METHODS: Rituximab PK and PD data were obtained from a randomized, double-blind, phase III clinical study (RTXM83-AC-01-11) in patients with diffuse large B-cell lymphoma (DLBCL) that received 375 mg/m2 intravenous RTXM83 or its reference product with CHOP regimen, every 3 weeks, for six cycles. Rituximab levels were quantified by Meso Scale Discovery assay. PK analysis was performed using NONMEM 7.3.0. The effect of disease and patient covariates on RXTM83 PK was investigated. Model was evaluated using visual predictive check and non-parametric bootstrap. RESULTS: In total, 251 DLBCL patients (127 and 124 in RXTM83-CHOP and rituximab-CHOP arms, respectively) and 5341 serum concentrations (2703 for RXTM83 and 2638 for rituximab, respectively) were available for the population PK analysis. The volume of distribution of the central compartment (V1) and clearance of RXTM83 were estimated at 3.19 L and 12.5 mL/h, respectively. Body surface area allowed to explain the interindividual variability for V1. A statistical analysis showed that systemic exposure (AUC and Cmax) of RTXM83 was similar to rituximab. The 90% confidence intervals for all pairwise comparisons were within the predefined bioequivalence interval of 0.80-1.25. PD similarity of B-cell depletion and recovery was also observed. CONCLUSIONS: The time course of RTXM83 was well characterized by the model developed. The systemic exposure of RTXM83 and its associated variability were similar to those for rituximab reference in DLBCL patients, demonstrating PK similarity. The PD similarity of RTXM83 and rituximab reference product was also demonstrated.

Citomegalovirus en pacientes inmunocomprometidos detectados por PCR en Paraguay del 2008 a 2015

Introducción: la infección por el citomegalovirus (CMV) se adquiere por contacto directo de secreciones infectadas, frecuente en países en desarrollo, produciendo estado de latencia, cronicidad e infección activa con replicación en ausencia de enfermedad clínica. En trasplantados se relaciona a desarrollo tardío de enfermedad y en recién nacidos (RN) a infección congénita. Objetivo: identificar el ADN del CMV por PCR (Reacción en cadena de la Polimerasa) cualitativa para confirmar la infección y el desarrollo de la enfermedad con la carga viral, en pacientes de diferentes servicios de salud con algún tipo de inmunosupresión en Paraguay. Metodología: diseño descriptivo, corte transversal realizado del 2008 a 2015. Se tomaron muestras de sangre con EDTA o líquido cefalorraquídeo (LCR). La extracción del ADN se realizó con Qiagen®, seguido de una Nested PCR, que detecta un producto de 78 pb, para carga viral el CMV artus de Qiagen® en equipo Rotor Gene por PCR en tiempo real. Resultados: se incluyeron 521 muestras, 416 para PCR cualitativa: 338 de sangre, 78 de LCR y 105 para cargas virales. Hombres fueron 247, mujeres 246 y RN 28; 303 del Hospital Central Instituto Previsión Social, 129 del Ministerio de Salud y 89 de hospitales privados. La PCR detectó el ADN del CMV en 248 (60%): 63% en sangre y 45% en LCR; 124 en mujeres y 107 en hombres, 17 en RN y 60 a 62 % en el grupo de 0 a 30 años. La carga viral resultó en 81 (77%): <10 copias/ml o no detectable, en 24 muestras se observaron valores desde 30 a 221.000 copias/mL. Conclusiones: se confirmó en Paraguay infección por CMV con la PCR cualitativa y el desarrollo de enfermedad por carga viral, en inmunocomprometidos: trasplantados, dializados, con HIV; en RN a infección congénita. La mayoría fue joven (0-30 años), de servicios públicos, instaurándose la profilaxis o terapia anticipada con el antiviral.

Introduction: The infection by cytomegalovirus (CMV) is acquired by direct contact with infected secretions, is frequent in developing countries, and produces latency state, chronicity and active infection with replication in the absence of clinical disease. In transplant recipients, it is related to a late development of the disease and in newborns (NB) to congenital infection. Objective: The aim was to identify CMV DNA by qualitative PCR (polymerase chain reaction) to confirm infection and the development of the disease by viral load in patients from different health services who have some form of immunosuppression in Paraguay. Methodology: Design: descriptive cross-sectional study from 2008 to 2015. We included EDTA blood samples or cerebrospinal fluid (CSF). The DNA extraction was made with Qiagen® followed by nested PCR which detects a product of 78 bp, Artus® CMV Rotor Gene Qiagen Test in a real time PCR equipment was used for viral load. Results: In total, 521 samples were included, 416 for qualitative PCR: 338 from blood, 78 from CSF and 105 for viral loads. There were 247 men, 246 women and 28 NBs; 303 from the Central Hospital of the Social Security Institute, 129 from the Ministry of Health and 89 from private hospitals. PCR detected CMV DNA in 248 (60%) samples: 63% in blood and 45% in CSF; 124 in women and 107 in men, 17 in NBs and 60-62% in the group of 0-30 years. Viral load resulted in 81 (77%) samples: <10 copies/mL or undetectable, in 24 samples values from 30 to 221,000 copies/mL. Conclusions: CMV infection was confirmed in Paraguay using qualitative PCR and development of the disease by viral load in immunocompromised patients: transplanted, dialyzed, and with HIV; in NBs due to congenital infection. Most patients were young (0-30 years) and from public services, viral prophylaxis or early therapy was implemented.

Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study.

Type 1 Gaucher disease (GD1), resulting from glucocerebrosidase deficiency, leads to splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone involvement. Current standard treatment is enzyme replacement therapy. Velaglucerase alfa is an enzyme replacement product for GD1, with the same amino acid sequence as naturally occurring human glucocerebrosidase. This multinational, Phase 3 trial evaluated the efficacy and safety of two doses of velaglucerase alfa in 25 treatment-naïve, anemic patients with GD1 (4-62 years of age), randomized to intravenous velaglucerase alfa 60 U/kg (n=12) or 45 U/kg body weight (n=13) every other week for 12 months. The primary endpoint was change from baseline in hemoglobin concentration in the 60 U/kg arm. At 12 months, mean hemoglobin concentrations increased from baseline [60 U/kg: +23.3%; +2.43 g/dL (P<0.001); 45 U/kg: +23.8%; +2.44 g/dL (P<0.001)], as did mean platelet counts [60 U/kg: +65.9%; +50.9 × 10(9) /L (P=0.002); 45 U/kg: +66.4%; +40.9 × 10(9) /L(P=0.01)]. Mean splenic volume decreased from baseline [60 U/kg: -50.4%, from 14.0 to 5.8 multiples of normal (MN) (P=0.003); 45 U/kg: -39.9%, from 14.5 to 9.5 MN (P=0.009)]. No drug-related serious adverse events or withdrawals were observed. One patient developed antibodies. Velaglucerase alfa was generally well tolerated and effective for adults and children with GD1 in this study. All disease-specific parameters measured demonstrated clinically meaningful improvements after 12 months.