Very Low-Dose Rituximab May Be Effective, Could Save Costs in Treating Non-Malignant Diseases

Rituximab is approved for use in hematological malignancies and in rheumatoid arthritis (RA), but is also used off-label in the treatment of antibody-dependent auto-immunological diseases. In off-label indications, alternative dosing schedules are sometimes used, though no dose-finding trials are available to help guide dosing in such diseases. A new study, published in Scientific Reports, investigated the dose-response relationship of rituximab at very low doses, and found that even doses as low as 1 mg/m² effectively depleted CD20 antigen-positive (CD20+) cells in healthy volunteers.

The study involved 2 trials. The first sought to investigate the most sensitive dose at which to compare rituximab with proposed biosimilars; the authors write that in vitro data suggest that the half maximal effective concentration (EC50) of rituximab in humans is ≤1 µg/ml, and that all regulatory approved doses of rituximab therefore exceed that plasma level 200- to 300-fold. Because of the low in vitro EC50, the authors hypothesized that “tiny fractions of authorized rituximab doses” would be sufficient to compare the effects of rituximab biosimilars.

In this first trial, 16 subjects were enrolled and received single infusions of rituximab 1 of 3 doses. Mean CD20+ cell counts decreased by approximately:

• 68% (95% CI; 57%-95%) after infusion of 0.1 mg/m² (n = 4)
• 74% (95% CI; 55%-82%) after infusion of 0.3 mg/m² (n = 4)
• 97% (95% CI; 94%-100%) after infusion of 1 mg/m² (n = 8)

Four weeks following infusion, CD20+ cells returned to approximately 60% of baseline levels in subjects who received a dose of 1 mg/m².

The second trial compared B lymphocyte depletion, immunogenicity, and safety of a proposed biosimilar rituximab product in an exploratory, randomized, double-blind, active controlled trial in 36 healthy volunteers. This trial included 2 dose cohorts.

At a dose of 0.1 mg/m²:

• Biosimilar rituximab depleted the CD20+ cell count by a mean of 48% (95% CI; 25%-84%)
• Reference rituximab depleted the CD20+ cell count by a mean of 55% (95% CI; 26%-85%)

At a dose of 0.3 mg/m²:

• Biosimilar rituximab depleted the CD20+ cell count by a mean of 81% (CI 95%; 67%-89%)
• Reference rituximab depleted the CD20+ cell count by a mean of 87% (CI 95%; 77%-96%).

After treatment with rituximab, 26 subjects tested positive for antibodies to rituximab (14 had received the biosimilar and 12 had received the reference product). In total, 106 non-serious, non-severe adverse events were reported in the 2 trials.

“The demonstrated high potency of rituximab at very low doses may have important implications for rituximab dosing in non-malignant diseases,” write the authors. “The ≥95% depletion of circulating B lymphocytes after infusion of 1 mg/m² rituximab, although of a transient nature, makes it conceivable that lower doses than the currently authorized (≥375 mg/m²) may suffice to deplete all B lymphocytes from the circulation and therefore may be equally effective.”

Also of interest are the cost savings that could be produced by treating non-malignant diseases with very low doses of rituximab or a biosimilar. The authors assume that rituximab’s price in the United Kingdom is approximately £1.75 (approximately $2.41) per 2 mg; thus, 2 doses of 1000 mg to treat RA could produce a cost of £3500 (approximately $4825). Two doses of 100 mg, which is the smallest vial size available, every 3 months would cost only £350 (approximately $414), which represents a cost reduction of 90%.

The authors of the study conclude that, based on their data, more cost-effective dosing regimens appear to be plausible for treating non-malignant diseases. While these regimens need to be tested in clinical trials involving patients, such alternative dosing could be useful for low-income countries that struggle to address the financial burden of treating patients using biologics.