Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab

Abstract

Aims: To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586.

Methods: A randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab-EU and rituximab-US responses using longitudinal nonlinear mixed effects models.

Results: The analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group-to-group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF-05280586 vs. rituximab-EU or rituximab-US lie outside the reference ranges were low.

Conclusions: No clinically meaningful differences were detected in DAS28 or ACR response between PF-05280586 and rituximab-EU or rituximab-US as the differences were within the pre-specified reference ranges.

Trial registration number: NCT01526057.

Keywords: Biosimilar; pharmacodynamics; pharmacokinetics.

Figure 1

Observed and predicted DAS28 change from baseline vs. time, by treatment. The light grey dashed lines and symbols represent individual patient response profiles, and solid lines represent the population predicted mean (PREDavg; black), observed median (red), geometric mean (orange), and individual predicted mean (iPREDavg; blue). The number of patients contributing to each time point is listed along the bottom of the x axis. DAS28, Disease Activity Score in 28 joints

Figure 2

Observed and predicted ACR20, ACR50 and ACR70 responder rates vs. time, by treatment. Red symbols and error bars represent the observed proportion and ±2 standard errors (SE), respectively, at each time point achieving the defined ACR response criteria. Solid black lines represent the population‐predicted proportion (Pop Mean) and blue lines are mean individual predicted proportion (iPREDavg). The number of patients contributing to each time point is listed along the bottom of the x axis. ACR20/50/70, American College of Rheumatology improvement in rheumatoid arthritis of 20%/50%/70%

Figure 3

Comparative assessment between PF‐05280586 and two rituximab comparators for DAS28cfb normalised AUEC. The reference range established from the two reference treatment groups for the signed difference approach (left panels) is defined by the 90% confidence interval (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. The reference range established from the two reference treatment groups for the absolute difference approach (right panels) is defined by the 90th percentile (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. Predictions within the comparative reference range implied that no meaningful difference was observed between PF‐05280586 and the reference. The point estimate (solid black vertical line) and distribution (histogram) of mean differences between the test and a single reference product is shown from this study for DAS28cfb. AUEC, area under the effect curve; DAS28cfb, Disease Activity Score in 28 joints change from baseline

Figure 4

Comparative assessment between PF‐05280586 and two rituximab comparators for ACR20 responder rates normalised AUEC. The reference range established from the two reference treatment groups for the signed difference approach (left panels) is defined by the 90% confidence interval (dashed red vertical lines) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. The reference range established from the two reference treatment groups for the absolute difference approach (right panels) is defined by the 90th percentile (single vertical dashed red line) of the distribution of time‐average normalised mean AUEC differences between rituximab‐EU vs. rituximab‐US. Predictions within the comparative reference range implied that no meaningful difference was observed between PF‐05280586 and the reference. The point estimate (solid black vertical line) and distribution (histogram) of mean differences between the test and a single reference product is shown from this study for ACR20. ACR20, American College of Rheumatology improvement in rheumatoid arthritis of 20%; AUEC, area under the effect curve

Figure 5

Clinical response profiles for three treatment groups before (left panels) and after (right panels) matching, based on swollen joint counts and patient's assessment of pain. Points represent mean (DAS28cfb, top) or proportion (ACR20, bottom). ACR20, American College of Rheumatology improvement in rheumatoid arthritis of 20%; DAS28cfb, Disease Activity Score in 28 joints change from baseline