Table 4.
Outcomes for intended copies of rituximab
| Study type/patients (n) | References | Outcome/time point | Biosimilara | Rituximaba | Statistical comparison | Quality assessment rating |
|---|---|---|---|---|---|---|
| IC Kikuzubam® | ||||||
| Nonclinical (cell based)/analytical | [57] | Functional assessment (in vitro) | (RTX/Reditux™) | Not evaluatedb | ||
| ADCC, ratio % | 80–125 | 80–125 | – | |||
| CDC (3 batches), ratio % | 98, 102, 112 | NR/81, 111, 108 | – | |||
| Composition | ||||||
| Peptide mapping | Same | Same | – | |||
| Glycan quantification | Same | Same | – | |||
| Mass spectrometry, intact mass | Heterogeneous | Heterogeneous | – | |||
| DSC analysis | Similar | Similar | – | |||
| Cation exchange, acid, % | 37.8 | 22.1/7.0 | – | |||
| Cation exchange, main, % | 56.6 | 68.5/20.6 | – | |||
| Cation exchange, basic, % | 5.6 | 9.4/72.4 | – | |||
| Hydrophobic interaction (main isoform), % | <3.0 | <2.0/<24.1 | – | |||
| Multiangle laser light scattering | Similar | Similar | – | |||
| IC Reditux™ | ||||||
| Clinical (PK/PD)/nonclinical (cell based)/NHL (3) | [58] | PK/PD (biodistribution) | D&B: good Score: 13/26 |
|||
| Liver, %, mean (SD) | 22.0 (8.0) at 96 h | NR | – | |||
| Kidney, %, mean (SD) | 3.8 (0.8) at 48 h | NR | – | |||
| Spleen, %, mean (SD) | 2.5 (1.3) at 48 h | NR | – | |||
| Heart, %, mean (SD) | 3.5 (1.5) at 24 h | NR | – | |||
| Functional assessment (in vitro) | ||||||
| Immunoreactivity | Highly specific <2% Nonspecific binding Immunoreactive fraction, 0.7984 |
NR | – | |||
| Apyrogenicity | Pyrogen free | NR | – | |||
| Post-marketing/observational (retrospective)/NR (223) | [60]; CA [59] CA [61] |
Efficacy | D&B: good Score: 16/26 |
|||
| CR, % | 82 | 75 | p = 0.294 | |||
| PR, % | 13 | 14 | p = 0.795 | |||
| CR/PR → progressed | 15 | 13 | p = 0.805 | |||
| Overall survival, % | 76 | 66 | p = 0.264 | |||
| Progression-free survival, % | 81 | 72 | p = 0.382 | |||
| Safety; grades 3 and 4 (n = 30): | ||||||
| Febrile neutropenia, % | 20 | 23 | p = 0.801 | |||
| Mucositis, % | 10 | 5 | p = 0.385 | |||
| Diarrhea, % | 10 | 20 | – | |||
| Peripheral neuropathy, % | 7 | 3 | – | |||
| Infusion reactions, % | 7 | 5 | p = 0.583 | |||
| Dilated cardiomyopathy, % | 3 | 3 | – | |||
| CMV viremia, % | 3 | 0 | – | |||
| Herpes zoster reactivation, % | 3 | 0 | – | |||
| Intestinal perforation, % | 0 | 3 | – | |||
| Urinary tract infection, % | 0 | 3 | – | |||
| Pneumonia, % | 0 | 8 | – | |||
| Post-marketing/observational (prospective)/DLBCL (133) (and rheumatoid arthritis, scleroderma, and dermatomyositis) | CA [62] | Safety | Modified D&B: fair Score: 4/12 |
|||
| All AEs, % | 14.3 | NA | – | |||
| Chills, % | 20 | NA | – | |||
| Headache, % | 16.7 | NA | – | |||
| Fever, % | 13.0 | NA | – | |||
| Urticaria, % | 10.0 | NA | – | |||
| Possibly treatment-related AEs, % | 66.7 | NA | – | |||
| Probable treatment-related AEs, % | 13.3 | NA | – | |||
| Proven treatment-related AEs, % | 20.0 | NA | – | |||
| All treatment-related AEs, % | 73.0 | NA | – | |||
| Mild AEs, % | 90.0 | NA | – | |||
| Moderate AEs, % | 6.7 | NA | – | |||
| Severe AEs, % | 3.3 | NA | – | |||
| Mortality, % | 0 | NA | – | |||
| Post-marketing/observational (prospective)/DLBCL (21) | CA [63] | Efficacy | Modified D&B: good Score: 5/12 |
|||
| B-cell count, day 3, median (SD) | 1.75 (0.27) cells/μL | NA | – | |||
| B-cell count, day 3, median (SD) | 5.56 (1.24) cells/μL | NA | – | |||
| Progression-free survival, % | 70.3 | NA | – | |||
| Safety | No toxicity | NA | – | |||
| PK/PD: | ||||||
| AUC, μg·h/mL, mean (SD) | 54,236 (47,555) | NA | – | |||
| C max, μg/mL, mean (SD) | 555.74 (141.46) | 408 (literature) | – | |||
| Half-life, d, mean (SD) | 10.9 (8.6) | 22 (literature) | – | |||
| Clearance, mL/h/kg, mean (SD) | 0.15 (0.16) | 0.14 (literature) | – | |||
| Volume distribution, L/kg, mean (SD) | 1.3 (0.64) | 2.7 (literature) | – | |||
| Residence time, d, mean (SD) | 2.78 (3.08) | NA | – | |||
| Nonclinical (cell based)/analytical | [57] | Functional assessment (in vitro): | (RTX/Kikuzubam®) | Not evaluatedb | ||
| ADCC, ratio % | 80–125 | 80–125 | – | |||
| CDC (3 batches), ratio % | 81, 111, 108 | NR/98, 102, 112 | – | |||
| Composition | ||||||
| Peptide mapping | Same | Same | – | |||
| Glycan quantification | Same | Same | – | |||
| Mass spectrometry, intact mass | Heterogeneous | Heterogeneous | – | |||
| DSC analysis | Similar | Similar | – | |||
| Cation exchange, acid, % | 7.0 | 22.1/37.8 | – | |||
| Cation exchange, main, % | 20.6 | 68.5/56.6 | – | |||
| Cation exchange, basic, % | 72.4 | 9.4/5.6 | – | |||
| Hydrophobic interaction (main isoform), % | <24.1 | <2.0/<3.0 | – | |||
| Multiangle laser light scattering | Similar | Similar | – | |||
| Nonclinical (cell based) | CA [64] | Safety (rat and rabbit cell lines) ADAb | Comparable | Comparable (USA/EU) | – | Not evaluatedb |
| Analytical | CA [65] | Composition | Not evaluatedb | |||
| IdeS digestion | Similar | Similar | – | |||
| Peptide mapping (trypsin and pepsin) | Similar | Similar | – | |||
| Isotope | Similar | Similar | – | |||
| Analytical | CA [66] | Composition | Not evaluatedb | |||
| SDS-PAGE | Similar | Similar | – | |||
| iCE | NR | NR | Sig. diff. | |||
| CE | NR | NR | Sig. diff. | |||
| CEX-HPLC | NR | NR | Sig. diff. | |||
ADAb antidrug antibody, ADCC antibody-dependent cellular cytotoxicity, AE adverse event, AUC area under the curve, CA conference abstract, CDC complement-dependent cytotoxicity, CE capillary electrophoresis, CEX-HPLC cation exchange–high-performance liquid chromatography, C max maximum concentration in serum, CMV cytomegalovirus, CR clinical remission, d day(s), D&B Downs and Black (tool), DLBCL diffuse large B-cell lymphoma, IC intended copy, iCE imaged capillary electrophoresis, DSC differential scanning calorimetry, NA not applicable, NHL non-Hodgkin lymphoma, NR not reported, PD pharmacodynamics, PK pharmacokinetics, PR partial remission, RTX rituximab, SD standard deviation, SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis, sig. diff. significantly different
aQualitative data for biosimilarity as stated by the corresponding study authors
bQuality assessment not conducted, because of the absence of validated tools specific for the study type, at the time of analysis