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Pharmacodynamic Effect: In patients with rheumatoid arthritis, treatment up to 6 months with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer (NK) cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent.
Following long-term treatment (median duration of XELJANZ treatment of approximately 5 years), CD4+ and CD8+ counts showed median reductions of 28% and 27%, respectively, from baseline. In contrast to the observed decrease after short-term dosing, CD16/56+ natural killer cell counts showed a median increase of 73% from baseline. CD19+ B cell counts showed no further increases after long-term XELJANZ treatment. These changes returned toward baseline after temporary discontinuation of treatment. There was no evidence of an increased risk of serious or opportunistic infections or herpes zoster at low values of CD4+, CD8+ or NK cell counts or high B cell counts.
Changes in total serum IgG, IgM, and IgA levels over 6-month XELJANZ dosing in patients with rheumatoid arthritis were small, not dose-dependent and similar to those seen on placebo.
After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the half-life.
Similar changes in T cells, B cells and serum CRP have been observed in patients with active psoriatic arthritis, although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active psoriatic arthritis.
Clinical Safety: In one large, randomized open-label PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor and on a stable dose of methotrexate, patients were treated with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily or a TNF inhibitor. Notably, in February 2019, the dose of tofacitinib in the 10 mg twice daily arm of the study was reduced to 5 mg twice daily after it was determined that the frequency of pulmonary embolism was increased in the tofacitinib 10 mg twice daily treatment arm versus the TNF inhibitor. Additionally, all-cause mortality was increased in the tofacitinib 10 mg twice daily treatment arm versus the TNF inhibitor and tofacitinib 5 mg twice daily treatment arms. In the final study data, patients in the tofacitinib 10 mg twice daily treatment arm were analyzed in their originally randomized treatment group. Results from final safety data from the study for selected events as follows.
Mortality: The IRs (95% CI) for all-cause mortality for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.50 (0.33, 0.74), 0.80 (0.57, 1.09), 0.65 (0.50, 0.82), and 0.34 (0.20, 0.54) events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.49 (0.81, 2.74), 2.37 (1.34, 4.18), and 1.91 (1.12, 3.27), respectively.
The IRs (95% CI) for deaths associated with infection for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.08 (0.02, 0.20), 0.18 (0.08, 0.35), 0.13 (0.07, 0.22), and 0.06 (0.01, 0.17) events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.30 (0.29, 5.79), 3.10 (0.84, 11.45), and 2.17 (0.62, 7.62), respectively.
The IRs (95% CI) for deaths associated with cardiovascular events for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.25 (0.13, 0.43), 0.41 (0.25, 0.63), 0.33 (0.23, 0.46), and 0.20 (0.10, 0.36) events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.26 (0.55, 2.88), 2.05 (0.96, 4.39), and 1.65 (0.81, 3.34), respectively.
The IRs (95% CI) for deaths associated with malignancies for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.10 (0.03, 0.23), 0.00 (0.00, 0.08), 0.05 (0.02, 0.12), and 0.02 (0.00, 0.11) events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 4.88 (0.57, 41.74), 0 (0.00, Inf), and 2.53 (0.30, 21.64), respectively.
The IRs (95% CI) for deaths associated with other causes (excluding infections, cardiovascular events, malignancies) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.08 (0.02, 0.20), 0.21 (0.10, 0.38), 0.14 (0.08, 0.23), and 0.06 (0.01, 0.17) events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.30 (0.29, 5.81), 3.45 (0.95, 12.54), and 2.34 (0.67, 8.16), respectively.
In XELJANZ clinical studies that included 10 mg twice a day, incidence rates for all-cause mortality in patients treated with XELJANZ 10 mg twice a day have not been higher than rates in patients treated with XELJANZ 5 mg twice a day. Mortality rates in patients treated with XELJANZ are similar to those reported for patients with RA, PsA, AS, pcJIA, and UC, treated with biologic therapies.
Infections: The IRs (95% CI) for all infections for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 41.74 (39.21, 44.39), 48.73 (45.82, 51.77), 45.02 (43.10, 47.01), and 34.24 (32.07, 36.53) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.20 (1.10, 1.31), 1.36 (1.24, 1.49), and 1.28 (1.18, 1.38), respectively.
The IRs (95% CI) for serious infections for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 2.86 (2.41, 3.37), 3.64 (3.11, 4.23), 3.24 (2.89, 3.62), and 2.44 (2.02, 2.92) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.17 (0.92, 1.50), 1.48 (1.17, 1.87), and 1.32 (1.07, 1.63), respectively.
The IRs (95% CI) for opportunistic infections for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.76 (0.54, 1.04), 0.91 (0.66, 1.22), 0.84 (0.67, 1.04), and 0.42 (0.26, 0.64) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.82 (1.07, 3.09), 2.17 (1.29, 3.66), and 1.99 (1.23, 3.22), respectively. The majority of the opportunistic infections in the XELJANZ treatment arms were opportunistic herpes zoster infections; a limited number of events with tuberculosis were also reported. Excluding opportunistic herpes zoster infections and tuberculosis, the IRs (95% CI) for all other opportunistic infections for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.08 (0.02, 0.20), 0.14 (0.06, 0.30), 0.11 (0.05, 0.20), and 0.06 (0.01, 0.17) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the hazard ratio (HR) (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.30 (0.29, 5.82), 2.40 (0.62, 9.29), and 1.84 (0.51, 6.59), respectively.
The IRs (95% CI) for herpes zoster (includes all herpes zoster events) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms) and TNF inhibitor were 3.75 (3.22, 4.34), 3.94 (3.38, 4.57), 3.84 (3.45, 4.26), and 1.18 (0.90, 1.52) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HR (95% CI) for herpes zoster with XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 3.17 (2.36, 4.27), 3.33 (2.48, 4.48), and 3.25 (2.46, 4.29), respectively.
Serious infections from non-interventional post approval safety study: Data from a non-interventional post approval safety study that evaluated tofacitinib in RA patients from a registry (US Corrona) showed that a numerically higher incidence rate of serious infection was observed for the 11 mg prolonged-release tablet administered once daily than the 5 mg film-coated tablet administered twice daily. Crude incidence rates (95% CI) (i.e., not adjusted for age or sex) from availability of each formulation at 12 months following initiation of treatment were 3.45 (1.93, 5.69) and 2.78 (1.74, 4.21) and at 36 months were 4.71 (3.08, 6.91) and 2.79 (2.01, 3.77) patients with events per 100 patient-years in the 11 mg prolonged-release tablet once daily and 5 mg film-coated tablet twice daily groups, respectively. The unadjusted hazard ratio was 1.30 (95% CI: 0.67, 2.50) at 12 months and 1.93 (95% CI: 1.15, 3.24) at 36 months for the 11 mg prolonged-release once daily dose compared to the 5 mg film-coated twice daily dose. Data is based on a small number of patients with events observed with relatively large confidence intervals and limited follow up time available in the 11 mg prolonged-release once daily dose group after 24 months.
Thromboembolism: Venous Thromboembolism: The IRs (95% CI) for VTE for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms) and TNF inhibitor were 0.33 (0.19, 0.53), 0.70 (0.49, 0.99), 0.51 (0.38, 0.67), and 0.20 (0.10, 0.37) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HR (95% CI) for VTE with XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.66 (0.76, 3.63), 3.52 (1.74, 7.12), and 2.56 (1.30, 5.05), respectively.
The IRs (95% CI) for PE for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms) and TNF inhibitor were 0.17 (0.08, 0.33), 0.50 (0.32, 0.74), 0.33 (0.23, 0.46), and 0.06 (0.01, 0.17) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HR (95% CI) for PE with XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 2.93 (0.79, 10.83), 8.26 (2.49, 27.43), and 5.53 (1.70, 18.02), respectively. In tofacitinib-treated patients where PE was observed, the majority (97%) had VTE risk factors.
The IRs (95% CI) for DVT for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms) and TNF inhibitor were 0.21 (0.11, 0.38), 0.31 (0.17, 0.51), 0.26 (0.17, 0.38), and 0.14 (0.06, 0.29) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HR (95% CI) for DVT with XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.54 (0.60, 3.97), 2.21 (0.90, 5.43), and 1.87 (0.81, 4.30), respectively.
In a post hoc exploratory biomarker analysis within a large, randomized PASS in RA patients who were 50 years or older with at least one additional cardiovascular risk factor, occurrences of subsequent VTEs were observed more frequently in tofacitinib-treated patients with D-dimer level ≥2× ULN at 12 months treatment versus those with D-dimer level <2× ULN. This observation was not identified in TNFi-treated patients. Interpretation is limited by the low number of VTE events and restricted D-dimer test availability (only assessed at Baseline, Month 12, and at the end of the study). In patients who did not have a VTE during the study, mean D-dimer levels were significantly reduced at Month 12 relative to Baseline across all treatment arms. However, D-dimer levels ≥2× ULN at Month 12 were observed in approximately 30% of patients without subsequent VTE events, indicating limited specificity of D-dimer testing in this study. Considering the data and the overall limitations of this post hoc exploratory biomarker analysis, there is limited utility of conducting D-dimer monitoring in the context of risk mitigation for VTE events.
Arterial Thromboembolism: The IRs (95% CI) for arterial thromboembolism (ATE) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms) and TNF inhibitor were 0.92 (0.68, 1.22), 0.94 (0.68, 1.25), 0.93 (0.75, 1.14), and 0.82 (0.59, 1.12) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HR (95% CI) for ATE with XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.12 (0.74, 1.70), 1.14 (0.75, 1.74), and 1.13 (0.78, 1.63), respectively.
Major Adverse Cardiovascular Events (MACE), Including Myocardial Infarction: MACE includes non-fatal myocardial infarction, non-fatal stroke, and cardiovascular deaths excluding fatal pulmonary embolism. The IRs (95% CI) for MACE for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.91 (0.67, 1.21), 1.05 (0.78, 1.38), 0.98 (0.79, 1.19), and 0.73 (0.52, 1.01) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.24 (0.81, 1.91), 1.43 (0.94, 2.18), and 1.33 (0.91, 1.94), respectively.
In the XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ, and TNFi treatment arms, there were a total of 19, 19, 38, and 11 patients with MI events, respectively. Of these totals, the number of patients with fatal MI events was 0, 3, 3, and 3, respectively, whereas the number of patients with non-fatal MI events was 19, 16, 35, and 8, respectively. Therefore, the IRs that follow are for non-fatal MI. The IRs (95% CI) for non-fatal MI for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.37 (0.22, 0.57), 0.33 (0.19, 0.53), 0.35 (0.24, 0.48), and 0.16 (0.07, 0.31) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 2.32 (1.02, 5.30), 2.08 (0.89, 4.86), and 2.20 (1.02, 4.75), respectively.
Malignancies Excluding NMSC: The IRs (95% CI) for malignancies excluding NMSC for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 1.13 (0.87, 1.45), 1.13 (0.86, 1.45), 1.13 (0.94, 1.35), and 0.77 (0.55, 1.04) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.47 (1.00, 2.18), 1.48 (1.00, 2.19), and 1.48 (1.04, 2.09), respectively.
The IRs (95% CI) for lymphoma for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.07 (0.02, 0.18), 0.11 (0.04, 0.24), 0.09 (0.04, 0.17), and 0.02 (0.00, 0.10) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 3.99 (0.45, 35.70), 6.24 (0.75, 51.86), and 5.09 (0.65, 39.78), respectively.
The IRs (95% CI) for lung cancer for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.23 (0.12, 0.40), 0.32 (0.18, 0.51), 0.28 (0.19, 0.39), and 0.13 (0.05, 0.26) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.84 (0.74, 4.62), 2.50 (1.04, 6.02), and 2.17 (0.95, 4.93), respectively.
NMSC: The IRs (95% CI) for NMSC for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.61 (0.41, 0.86), 0.69 (0.47, 0.96), 0.64 (0.50, 0.82), and 0.32 (0.18, 0.52) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.90 (1.04, 3.47), 2.16 (1.19, 3.92), and 2.02 (1.17, 3.50), respectively.
The IRs (95% CI) for basal cell carcinoma for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.37 (0.22, 0.58), 0.33 (0.19, 0.54), 0.35 (0.24, 0.49), and 0.26 (0.14, 0.44) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.43 (0.71, 2.90), 1.28 (0.61, 2.66), and 1.36 (0.72, 2.56), respectively.
The IRs (95% CI) for cutaneous squamous cell carcinoma for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.29 (0.16, 0.48), 0.45 (0.29, 0.69), 0.37 (0.26, 0.51), and 0.16 (0.07, 0.31) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.82 (0.77, 4.30), 2.86 (1.27, 6.43), and 2.32 (1.08, 4.99), respectively.
Gastrointestinal Perforations: The IRs (95% CI) for gastrointestinal perforations for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 0.17 (0.08, 0.33), 0.10 (0.03, 0.24), 0.14 (0.08, 0.23), and 0.08 (0.02, 0.20) patients with events per 100 PYs, respectively. Compared with TNF inhibitor, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 2.20 (0.68, 7.15), 1.29 (0.35, 4.80), and 1.76 (0.58, 5.34), respectively.
Fractures: The IRs (95% CI) for fractures for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, all XELJANZ (combines 5 mg twice daily and 10 mg twice daily treatment arms), and TNF inhibitor were 2.79 (2.34, 3.30), 2.87 (2.40, 3.40), 2.83 (2.50, 3.19) and 2.27 (1.87, 2.74) patients with events per 100 PYs, respectively. Compared with TNFi, the HRs (95% CI) for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and all XELJANZ were 1.23 (0.96, 1.58), 1.26 (0.97, 1.62) and 1.24 (0.99, 1.55), respectively.
Laboratory tests: Liver enzyme tests: The percentages of patients with at least one post-baseline ALT elevation >1x ULN, 3x ULN, and 5x ULN for the XELJANZ 5 mg twice daily treatment arm were 52.83, 6.01, and 1.68, respectively. The percentages for the XELJANZ 10 mg twice daily treatment arm were 54.46, 6.54, and 1.97, respectively. The percentages for all XELJANZ (combines XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily) were 53.64, 6.27, and 1.82, respectively. The percentages for the TNF inhibitor treatment arm were 43.33, 3.77, and 1.12, respectively.
The percentages of patients with at least one post-baseline AST elevation >1x ULN, 3x ULN, and 5x ULN for the XELJANZ 5 mg twice daily treatment arm were 45.84, 3.21, and 0.98, respectively. The percentages for the XELJANZ 10 mg twice daily treatment arm were 51.58, 4.57, and 1.62, respectively. The percentages for all XELJANZ (combines XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily) were 48.70, 3.89, and 1.30, respectively. The percentages for the TNF inhibitor treatment arm were 37.18, 2.38, and 0.70, respectively.
Lipids: At 12 months, in the XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and TNF inhibitor treatment arms, the mean percent increase in LDL cholesterol was 13.80, 17.04, and 5.50, respectively. At 24 months, the mean percent increase was 12.71, 18.14, and 3.64, respectively.
At 12 months, in the XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and TNF inhibitor treatment arms, the mean percent increase in HDL cholesterol was 11.71, 13.63, and 2.82, respectively. At 24 months, the mean percent increase was 11.58, 13.54, and 1.42, respectively.
Clinical Efficacy: Rheumatoid Arthritis: The efficacy and safety of XELJANZ were assessed in six randomized, double-blind, controlled multicenter studies in patients >18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 tender and 6 swollen joints at randomization (4 swollen and tender joints for Study II). XELJANZ, 5 or 10 mg twice daily, was given as monotherapy (Study I) and in combination with DMARDs (Study II) in patients with an inadequate response to those drugs, and in combination with MTX in patients with either an inadequate response to MTX (Studies III and Study IV) or inadequate efficacy or lack of tolerance to at least one approved TNF-inhibiting biologic agent (Study V).
Study I was a 6-month monotherapy study in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (non-biologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) <2.6.
Study II was a 12-month study in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a non-biologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments, such as azathioprine or cyclosporine). At the Month 3 visit, non-responding patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3 and rates of DAS28-4(ESR) <2.6 at Month 6.
Study III was a 12-month study in which 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) <2.6 at Month 6.
Study IV was a 2-year study with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) <2.6 at Month 6.
Study V was a 6-month study in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) <2.6.
Study VI was a 2-year monotherapy study with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active rheumatoid arthritis received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks from 10 to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde mTSS at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.
Clinical Response: ACR response: The percentages of XELJANZ-treated patients achieving ACR20, ACR50 and ACR70 responses in Studies I, II, IV, V and VI are shown in Table 1. In all studies, patients treated with either 5 or 10 mg twice daily XELJANZ had statistically significant ACR20, ACR50 and ACR70 response rates at Month 3 and Month 6 vs. placebo (or vs. MTX in Study VI) treated patients.
In Study IV, ACR20/50/70 response rates at Month 12 were maintained through Month 24.
In Study VI (Table 1), the difference from MTX in both tofacitinib groups, in achieving ACR20, ACR50 and ACR70 response rates was statistically significant at all timepoints (p≤0.0001). Tofacitinib, administered as monotherapy in MTX-naïve patients, significantly improved RA signs and symptoms in comparison to MTX. Efficacy observed with tofacitinib was sustained through Month 24.
In Studies I, II, and V, improvement in ACR20 response rate vs. placebo was observed within 2 weeks.
During the 3-month (Studies I and V) and 6-month (Studies II, III, and IV) controlled portions of the studies, patients treated with XELJANZ at a dose of 10 mg twice daily generally had higher response rates compared to patients treated with XELJANZ 5 mg twice daily. In Study III, the primary endpoints were the proportion achieving an ACR20 response at Month 6; change in HAQ-DI at Month 3, and DAS28-4(ESR) <2.6 at Month 6. The data for these primary outcomes were 51.5, 52.6, 47.2 and 28.3%; -0.55, -0.61, -0.49 and -0.24; and 6.2%, 12.5%, 6.7% and 1.1% for the 5 mg twice daily XELJANZ, 10 mg twice daily XELJANZ, adalimumab 40 mg subcutaneously every other week and placebo groups, respectively. For a pre-specified secondary endpoint, the ACR70 response rates at Month 6 for the 5 mg twice daily and 10 mg twice daily XELJANZ groups were significantly greater than adalimumab 19.9%, 21.9% and 9.1%, respectively.
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, or disease status. Time to onset was rapid (as early as Week 2 in Studies I, II and V) and the magnitude of response continued to improve with duration of treatment. As with the overall ACR response in patients treated with 5 mg or 10 mg twice daily XELJANZ, each of the components of the ACR response was consistently improved from baseline including: tender and swollen joint counts; patient and physician global assessment; disability index scores; pain assessment and CRP compared to patients receiving placebo plus MTX or other DMARDs in all studies.
DAS28-4(ESR) response: Patients in the Phase 3 studies had a mean Disease Activity Score (DAS28-4[ESR]) of 6.1-6.7 at baseline. Significant reductions in DAS28-4(ESR) from baseline (mean improvement) of 1.8-2.0 and 1.9-2.2 were observed in 5 mg and 10 mg XELJANZ-treated patients, respectively, compared to placebo-treated patients (0.7-1.1) at 3 months. The proportion of patients achieving a DAS28 clinical remission (DAS28-4(ESR) <2.6) in Studies II, III and IV was significantly higher in patients receiving 5 mg or 10 mg XELJANZ (6%-9% and 13%-16%, respectively) compared to 1%-3% of placebo patients at 6 months. In Study III, the percentages of patients achieving DAS28-4(ESR) <2.6 observed for XELJANZ 5 mg twice daily, 10 mg twice daily, and adalimumab at Month 6 were 6.2%, 12.5%, and 6.7%, respectively.
In a pooled analysis of the Phase 3 studies, the 10 mg twice daily dose provided increased benefit over the 5 mg twice daily dose in multiple measures of signs and symptoms: improvement from baseline (ACR20, ACR50, and ACR70 response rates), and achievement of targeted disease activity state (either DAS28-4(ESR) <2.6 or ≤3.2). Greater benefits of 10 mg versus 5 mg were shown in the more stringent measures (i.e., ACR70 and DAS28-4 (ESR) <2.6 response rates). (See Table 1.)
Click on icon to see table/diagram/imageThe results of the proportion of patients with an ACR Response for Studies I, II, IV, V and VI are shown in Table 1. Similar results were observed in Study III.
The results of the components of the ACR response criteria for Studies IV and V are shown in Table 2. Similar results were observed in Studies I, II and III. (See Table 2.)
Click on icon to see table/diagram/imageThe percent of ACR20 responders by visit for Study IV is shown in Figure 1. Similar responses were observed in Studies I, II, III and V. (See Figure 1.)
Click on icon to see table/diagram/imageRadiographic Response: Two studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study IV and Study VI, inhibition of progression of structural joint damage was assessed radiographically and expressed as mean change from baseline in mTSS and its components, the erosion score and joint space narrowing (JSN) score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0.5) was also assessed.
In Study IV, XELJANZ 10 mg twice daily plus background MTX resulted in significantly greater inhibition of the progression of structural damage compared to placebo plus MTX at Months 6 and 12. When given at a dose of 5 mg twice daily, XELJANZ plus MTX exhibited similar effects on mean progression of structural damage (not statistically significant). Analysis on erosion and JSN score were consistent with overall results. These results are shown in Table 3.
In the placebo plus MTX group, 78% of patients experienced no radiographic progression at Month 6 compared to 89% and 87% of patients treated with XELJANZ 5 or 10 mg twice daily respectively, plus MTX, both significant vs. placebo plus MTX. (See Table 3.)
Click on icon to see table/diagram/imageIn Study VI, XELJANZ monotherapy resulted in significantly greater inhibition of the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 4, which was also maintained at Month 24. Analyses of erosion and JSN scores were consistent with overall results.
In the MTX group, 70% of patients experienced no radiographic progression at Month 6 compared to 84% and 90% of patients treated with XELJANZ 5 or 10 mg twice daily respectively, both significant vs. MTX. (See Table 4.)
Click on icon to see table/diagram/imagePhysical Function Response and Health Related Outcomes: Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 or 10 mg twice daily demonstrated significantly greater improvement from baseline in physical functioning compared to placebo at Month 3 (Studies I, II, III, and V) and Month 6 (Studies II and III). XELJANZ 5 or 10 mg twice daily-treated patients exhibited significantly greater improved physical functioning compared to placebo as early as Week 2 in Studies I and II. In Study III, mean HAQ-DI improvements were maintained to 12 months in XELJANZ-treated patients. Mean HAQ-DI improvements were maintained for 36 months in the ongoing open-label extension studies. Compared with adalimumab-treated patients, at Month 3, patients in the XELJANZ 5 mg twice daily had similar decreases from baseline in HAQ-DI values and patients in 10 mg twice daily group had significantly greater decreases in HAQ-DI. The mean change in HAQ-DI from baseline to Month 3 in Studies I to VI are shown in Table 5. (See Table 5.)
Click on icon to see table/diagram/imageHealth-related quality of life was assessed by the Short Form Health Survey (SF-36) in all 5 studies. In these studies, patients receiving XELJANZ 10 mg twice daily demonstrated significantly greater improvement from baseline compared to placebo in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS) at Month 3. Both XELJANZ-treated groups exhibited significantly greater improvement from baseline compared to placebo in all 8 domains as well as PCS and MCS at Month 3 in Studies I, IV, and V. In Studies III and IV, mean SF-36 improvements were maintained to 12 months in XELJANZ-treated patients.
Improvement in fatigue was evaluated by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale at Month 3 in all studies. Patients receiving XELJANZ 5 or 10 mg twice daily demonstrated significantly greater improvement from baseline in fatigue compared to placebo in all 5 studies. In Studies III and IV, mean FACIT-F improvements were maintained to 12 months in XELJANZ-treated patients.
Improvement in sleep was assessed using the Sleep Problems Index I and II summary scales of the Medical Outcomes Study Sleep (MOS-Sleep) measure at Month 3 in all studies. Patients receiving XELJANZ 5 or 10 mg twice daily demonstrated significantly greater improvement from baseline in both scales compared to placebo in Studies II, III, and IV. In Studies III and IV, mean improvements in both scales were maintained to 12 months in XELJANZ-treated patients.
Improvement in productivity was evaluated using the Work Limitations Questionnaire (WLQ) scale at Month 3 in all studies. Patients receiving XELJANZ 10 mg twice daily demonstrated significantly greater improvement from baseline in the Overall Output Summary Scale compared to placebo in Studies III, IV, and V. In Studies III and IV, mean Overall Output improvements were maintained to 12 months in XELJANZ 10 mg twice daily-treated patients.
Durability of clinical responses: Durability of effect was assessed by ACR20, ACR50, ACR70 response rates, mean HAQ-DI, and mean DAS28-4(ESR) in the three Phase 3 DMARD IR studies with duration of at least one year. Efficacy was maintained in all tofacitinib treatment groups through to the end of the studies. Evidence of persistence of efficacy with tofacitinib treatment for up to 6 years is also provided from data in a large, randomized PASS in RA patients 50 years and older with at least one additional CV risk factor, as well as in completed open-label, long-term follow-up studies up to 8 years.
Psoriatic Arthritis: The XELJANZ clinical development program to assess efficacy and safety in patients with psoriatic arthritis included 2 multicenter, randomized, double-blind, placebo-controlled confirmatory trials in 816 patients 18 years of age and older. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender/painful joints and at least 3 swollen joints, and active plaque psoriasis. Patients with different psoriatic arthritis subtypes (not mutually exclusive) were enrolled across the 2 clinical trials, including <5 joints or asymmetric involvement (21%), ≥5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had a diagnosis of psoriatic arthritis for a median of 5.5 years (range 3.0-6.0 years). At baseline, 80%, 53%, and 69% of patients had enthesitis, dactylitis, and total psoriatic body surface area (BSA) ≥3%, respectively. All patients were required to receive treatment with a stable dose of conventional synthetic DMARDs (csDMARDs; 79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other csDMARDs) and were allowed to receive a stable low dose of oral corticosteroids (21% received equivalent to ≤10 mg/day of prednisone) and/or nonsteroidal anti-inflammatory drugs (NSAIDs; 57% received). In both clinical trials, the primary endpoints were the ACR20 response and the change in HAQ DI at Month 3.
Study PsA-I was a 12-month clinical trial in 422 patients who had an inadequate response to a csDMARD (67% and 33% were inadequate responders to 1 csDMARD and ≥2 csDMARDs, respectively) and who were naïve to treatment with a TNF-inhibitor biologic DMARD (TNFi). Patients were randomized in a 2:2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background csDMARD treatment. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.
Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNFi (66%, 19% and 15% were inadequate responders to 1 TNFi, 2 TNFi, and ≥3 TNFi, respectively). Patients were randomized in a 2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background csDMARD treatment. At the Month 3 visit, placebo patients were advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily as in Study PsA-I.
Clinical Response: Signs and Symptoms: At Month 3, patients treated with either XELJANZ 5 mg or 10 mg twice daily had higher (p≤0.05) response rates versus placebo for ACR20, ACR50, and ACR70 in Study PsA-I and for ACR20 and ACR50 in Study PsA-II; ACR70 response rates were also higher for both XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Table 6). Examination of age, sex, race, baseline disease activity and psoriatic arthritis subtype did not identify differences in response to XELJANZ. The number of patients with arthritis mutilans was too small to allow meaningful assessment. (See Table 6.)
Click on icon to see table/diagram/imageAs with the ACR responses, in patients treated with XELJANZ 5 mg or 10 mg twice daily in Studies PsA-I and PsA-II, each of the components of the ACR response was consistently improved from baseline at Month 3 including tender/painful and swollen joint counts, patient assessment of arthritis pain, patient and physician’s global assessment of arthritis, HAQ-DI, and CRP compared to patients receiving placebo (Table 7). (See Table 7.)
Click on icon to see table/diagram/imageThe percentage of ACR20 responders by visit for Studies PsA-I and PsA-II is shown in Figure 2. In XELJANZ-treated patients in both Studies PsA-I and PsA-II, significantly higher ACR20 response rates were observed within 2 weeks compared to placebo (Figure 2). After Month 3, ACR response rates were maintained or improved up to Month 6 (Studies PsA-I and PsA-II) and Month 12 (Study PsA-I). (See Figure 2.)
Click on icon to see table/diagram/imageIn patients with enthesitis at baseline, evidence of benefit in enthesitis was observed with XELJANZ treatment. In Study PsA-I, the change from baseline in Leeds Enthesitis Index score was -0.8, -1.5, -1.1, and -0.4 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, and placebo, respectively, at Month 3; and -1.7, -1.6, and -1.6 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and adalimumab 40 mg subcutaneously once every 2 weeks, respectively, at Month 12. In Study PsA-II, the change from baseline in Leeds Enthesitis Index score was -1.3, -1.3, and -0.5 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and placebo, respectively, at Month 3; and -1.5 and -1.6 for XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily, respectively, at Month 6.
In Study PsA-I, resolution of enthesitis at Month 3 occurred in 33.3%, 40.6%, 47.4%, and 21.5% of patients on XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, and placebo, respectively. In Study PsA-II, resolution of enthesitis at Month 3 occurred in 39.8%, 32.3%, and 21.5% of patients on XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and placebo, respectively.
In patients with dactylitis at baseline, evidence of benefit in dactylitis was observed with XELJANZ treatment. In Study PsA-I, the change from baseline in Dactylitis Severity Score was -3.5, -5.5, -4.0, and -2.0 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, and placebo, respectively, at Month 3; and -7.4, -7.5, and -6.1 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and adalimumab 40 mg subcutaneously once every 2 weeks, respectively, at Month 12. In Study PsA-II, the change from baseline in Dactylitis Severity Score was -5.2, -5.4, and -1.9 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and placebo, respectively, at Month 3; and -6.0 and -6.0 for XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily, respectively, at Month 6.
In Study PsA-I, resolution of dactylitis at Month 3 occurred in 34.4%, 60.0%, 46.6%, and 32.8% of patients on XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, and placebo, respectively. In Study PsA-II, resolution of dactylitis at Month 3 occurred in 51.5%, 50.8%, and 28.6% of patients on XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and placebo, respectively.
Evidence of benefit in skin manifestations of psoriatic arthritis was assessed by PASI75 (≥75% improvement from baseline in Psoriasis Area and Severity Index), in patients with active psoriatic arthritis who had total psoriatic BSA ≥3%. In PsA Study-I, PASI75 responder rates at Month 3 were higher for XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily versus placebo. In PsA Study-II, PASI75 responder rates at Month 3 were higher (not statistically significant) for XELJANZ 5 mg twice daily and higher for XELJANZ 10 mg twice daily versus placebo. After Month 3, benefit in this domain was maintained or improved up to Month 6 (Studies PsA-I and PsA-II) and Month 12 (Study PsA-I).
Psoriatic arthritis disease activity was also measured by Minimal Disease Activity (MDA) and Psoriatic Arthritis Disease Activity Score (PASDAS). In Study PsA-I, the MDA rates at Month 3 were in 26%, 26%, 25%, and 7% in patients on XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, and placebo, respectively. In Study PsA-II, the MDA rates at Month 3 were in 23%, 21%, and 15% in patients on XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and placebo, respectively. After Month 3 in XELJANZ-treated patients, MDA rates were maintained or improved up to Month 6 (Studies PsA-I and PsA-II) and Month 12 (Study PsA-I).
In Study PsA-I, the change from baseline in PASDAS at Month 3 was -2.0, -2.4, -2.2, and -1.2 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, and placebo, respectively. In Study PsA-II, the change from baseline in PASDAS at Month 3 was -1.9, -2.1, and -0.8 for XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and placebo, respectively. After Month 3 in XELJANZ-treated patients, the change from baseline in PASDAS was maintained or improved up to Month 6 (Studies PsA-I and PsA-II) and Month 12 (Study PsA-I).
Physical Function: Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater improvement (p≤0.05) from baseline in physical functioning compared to placebo at Month 3 (Table 8). HAQ-DI improvement from baseline in XELJANZ-treated patients was maintained or improved through Month 6 (Studies PsA-I and PsA-II) and Month 12 (Study PsA-I). (See Table 8.)
Click on icon to see table/diagram/imageThe HAQ-DI responder rate (response defined as having decrease from baseline of ≥0.35) at Month 3 in Studies PsA-I and PsA-II was 53% and 50%, respectively in patients receiving XELJANZ 5 mg twice daily, 55% and 41%, respectively in patients receiving XELJANZ 10 mg twice daily, 31% and 28%, respectively in patients receiving placebo, and 53% in patients receiving adalimumab 40 mg subcutaneously once every 2 weeks (Study PsA-I only).
Other Health-Related Outcomes: General health status was assessed by the Short Form health survey (SF-36). In Studies PsA-I and PsA-II, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily had greater improvement from baseline compared to placebo in Physical Component Summary (PCS) score and physical functioning domain score and no worsening in Mental Component Summary (MCS) score at Month 3. Improvements in SF-36 were maintained through Month 6 (Studies PsA-I and PsA-II) and Month 12 (Study PsA-I).
Health outcomes related to fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). In Studies PsA-I and PsA-II, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily had greater improvement from baseline compared to placebo in the FACIT-F total score, experience domain score, and impact domain score at Month 3.
Improvements in the FACIT-F were maintained through Month 6 (Studies PsA-I and PsA II) and Month 12 (Study PsA-I).
Radiographic Response: In Study PsA-I, progression of structural joint damage was assessed radiographically utilizing the van der Heijde modified Total Sharp Score (mTSS) and the proportion of patients with radiographic progression (mTSS increase from baseline greater than 0.5) was assessed at Month 12. At Month 12, 96%, 95%, and 98% of patients receiving XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, and adalimumab 40 mg SC every 2 weeks, respectively, did not have radiographic progression (mTSS increase from baseline less than or equal to 0.5).
Ankylosing Spondylitis: The XELJANZ clinical development program to assess the efficacy and safety included one placebo-controlled confirmatory trial (Study AS-I) and one dose-ranging trial (Study AS-II). Patients had active disease as defined by both Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and back pain score (BASDAI question 2) of greater or equal to 4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or DMARD therapy.
Confirmatory Trial (Study AS-I): Study AS-I was a randomized, double-blind, placebo-controlled, 48-week treatment clinical trial in 269 adult patients who had an inadequate response (inadequate clinical response or intolerance) to at least 2 NSAIDs. Patients were randomized and treated with XELJANZ 5 mg twice daily or placebo for 16 weeks of blinded treatment and then all were advanced to XELJANZ 5 mg twice daily for an additional 32 weeks. The primary endpoint was to evaluate the proportion of patients who achieved an ASAS20 response at Week 16.
Approximately 7% and 21% of patients used concomitant methotrexate or sulfasalazine, respectively, from baseline to Week 16. Patients were allowed to receive a stable low dose of oral corticosteroids (8.6% received) and/or NSAIDs (81.8% received) from baseline to Week 48. Twenty-two percent of patients had an inadequate response to 1 or 2 TNF blockers.
Clinical Response: Patients treated with XELJANZ 5 mg twice daily achieved greater improvements in ASAS20, ASAS40, and ASAS 5/6 responses compared to placebo at Week 16 (Table 9). The responses were maintained from Week 16 through Week 48 in patients receiving XELJANZ 5 mg twice daily. (See Table 9.)
Click on icon to see table/diagram/imageThe improvements in the components of the ASAS response and other measures of disease activity were higher in XELJANZ 5 mg twice daily compared to placebo at Week 16 as shown in Table 10. The improvements were maintained from Week 16 through Week 48 in patients receiving XELJANZ 5 mg twice daily. (See Table 10.)
Click on icon to see table/diagram/imageImprovement in ASAS20 response was first observed at Week 2. The percentage of patients achieving ASAS20 response by visit is shown in Figure 3. (See Figure 3.)
Click on icon to see table/diagram/imageOther Health-Related Outcomes: Patients treated with XELJANZ 5 mg twice daily achieved greater improvements from baseline in Ankylosing Spondylitis Quality of Life (ASQoL) (-4.0 vs -2.0) and Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total score (6.5 vs 3.1) compared to placebo-treated patients at Week 16 (p<0.001). Patients treated with XELJANZ 5 mg twice daily achieved consistently greater improvements from baseline in the Short Form health survey version 2 (SF- 36v2), Physical Component Summary (PCS), Physical Functioning, Role-Physical, Bodily Pain, General Health, and Social Functioning domains compared to placebo-treated patients at Week 16.
The improvements of FACIT-F Total score were maintained from Week 16 through Week 48 in patients receiving XELJANZ 5 mg twice daily. The improvements of ASQoL, and SF 36v2 PCS, Physical Functioning, Role-Physical, Bodily Pain, General Health, and Social Functioning domains were maintained at Week 48 in patients receiving XELJANZ 5 mg twice daily.
Ulcerative Colitis: The XELJANZ Phase 3 clinical development program for the ulcerative colitis indication included 3 confirmatory studies (Study UC-I, Study UC-II, and Study UC-III) and an open-label long-term extension study (Study UC-IV).
Confirmatory Studies: The safety and efficacy of XELJANZ to induce and maintain remission were assessed in 3 multicenter, double-blind, randomized, placebo-controlled studies: 2 identical induction studies (8 weeks duration; Study UC-I and Study UC-II) and 1 maintenance study (52 weeks duration; Study UC-III). These pivotal studies included adult patients with moderately to severely active ulcerative colitis (total Mayo score of 6 to 12, with an endoscopy subscore of at least 2, and rectal bleeding subscore of at least 1) and who had failed or were intolerant to at least 1 of the following treatments: oral or intravenous corticosteroids, azathioprine, 6-MP or TNF inhibitor. The disease activity was assessed by Mayo scoring index (0 to 12) which consisted of 4 subscores (0 to 3 for each subscore): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 was defined by marked erythema, absent vascular pattern, any friability, and erosions; an endoscopy subscore of 3 was defined by spontaneous bleeding and ulceration. Patients who completed Study UC-I or Study UC-II and achieved clinical response were eligible for re-randomization into Study UC-III.
Patients were permitted to use stable doses of oral aminosalicylates and corticosteroids (prednisone daily dose up to 25 mg equivalent) during the studies. Corticosteroid tapering was required upon entrance into Study UC-III. XELJANZ was administered as monotherapy (i.e., without concomitant use of biologics and immunosuppressants) for ulcerative colitis during the studies.
In addition to the previously mentioned studies, safety and efficacy of XELJANZ were also assessed in an open-label long-term extension study (Study UC-IV). Patients who completed 1 of the induction studies (Study UC-I or Study UC-II) but did not achieve clinical response or patients who completed or withdrew early due to treatment failure in the maintenance study (Study UC-III) were eligible for Study UC-IV. Patients from Study UC-I or Study UC-II who did not achieve clinical response after 8 weeks in Study UC-IV were to be discontinued from Study UC-IV. Corticosteroid tapering was required upon entrance into Study UC-IV.
Induction Studies (Study UC-I and Study UC-II): In Study UC-I and Study UC-II, 1139 patients were randomized (598 and 541 patients respectively) to XELJANZ 10 mg twice daily or placebo with a 4:1 treatment allocation ratio. In Study UC-I and Study UC-II, 51.7%, 73.2% and 71.9% of patients had previously failed or were intolerant to TNF inhibitors (51.3% in Study UC-I and 52.1% in Study UC-II), corticosteroids (74.9% in Study UC-I and 71.3% in Study UC-II), and/or immunosuppressants (74.1% in Study UC-I and 69.5% in Study UC-II), respectively. At baseline, 46.1% of patients were receiving oral corticosteroids as concomitant treatment for ulcerative colitis (45.5% in Study UC-I and 46.8% in Study UC-II). The baseline clinical characteristics were generally similar between the XELJANZ treated patients and patients receiving placebo.
The primary endpoint of Study UC-I and Study UC-II was the proportion of patients in remission at Week 8, and the key secondary endpoint was the proportion of patients with improvement of endoscopic appearance of the mucosa at Week 8. Remission was defined as clinical remission (a total Mayo score ≤2 with no individual subscore >1) and rectal bleeding subscore of 0. Improvement of endoscopic appearance of the mucosa was defined as endoscopy subscore of 0 or 1.
The efficacy results of Study UC-I and Study UC-II based on the centrally read endoscopy results are shown in Table 11. A significantly greater proportion of patients treated with XELJANZ 10 mg twice daily achieved remission, improvement of endoscopic appearance of the mucosa, and clinical response at Week 8 compared to placebo in both studies. (See Table 11.)
Click on icon to see table/diagram/imageThe efficacy results based on the endoscopic readings at the study sites were consistent with the results based on the central endoscopy readings.
The results of the individual studies Study UC-I and Study UC-II were similar. Pooled data provide a more precise estimate of the treatment difference between XELJANZ 10 mg twice daily and placebo at Week 8: 11.6% (95% CI, 7.7% - 15.5%) in remission and 16.3% (95% CI, 11.0% - 21.6%) with improvement of endoscopic appearance of the mucosa.
In both of the subgroups of patients with or without prior TNF inhibitor failure, a greater proportion of patients treated with XELJANZ 10 mg twice daily achieved remission and improvement of endoscopic appearance of the mucosa at Week 8 as compared to placebo. This treatment difference was consistent between the 2 subgroups (Table 12). (See Table 12.)
Click on icon to see table/diagram/imageChanges from baseline in rectal bleeding and stool frequency subscores were assessed at each visit from Study UC-I and Study UC-II and are shown in Figure 4. Significant improvements from baseline in both rectal bleeding and stool frequency were observed in patients treated with XELJANZ compared to placebo. The treatment differences in rectal bleeding and stool frequency between XELJANZ 10 mg twice daily and placebo were significant as early as Week 2, the earliest scheduled study visit, and at each visit thereafter. (See Figure 4.)
Click on icon to see table/diagram/imageChanges from baseline in partial Mayo score from pooled data of Study UC-I and Study UC-II are shown in Figure 5. Significant improvements from baseline in partial Mayo score were observed in patients treated with XELJANZ 10 mg twice daily compared to placebo at each study visit. The treatment differences in partial Mayo score between XELJANZ 10 mg twice daily and placebo were significant as early as Week 2, similar to rectal bleeding and stool frequency as observed in the individual induction studies. (See Figure 5.)
Click on icon to see table/diagram/imageMaintenance Study (Study UC-III): A total of 593 patients who completed 8 weeks in 1 of the induction studies and achieved clinical response entered into Study UC-III; 179 (30.2%) patients were in remission at baseline of Study UC-III. Patients were re-randomized to XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, or placebo for 52 weeks with 1:1:1 treatment allocation ratio. Corticosteroid tapering was mandatory for patients who were receiving corticosteroids at baseline.
At baseline of Study UC-III, 289 (48.7%) patients were receiving oral corticosteroids; 265 (44.7%), 445 (75.0%), and 413 (69.6%) patients had previously failed or were intolerant to TNF inhibitor therapy, corticosteroids, and immunosuppressants, respectively.
The primary endpoint in Study UC-III was the proportion of patients in remission at Week 52. There were 2 key secondary endpoints: the proportion of patients with improvement of endoscopic appearance at Week 52, and the proportion of patients with sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline of Study UC-III.
The efficacy results of Study UC-III based on the centrally read endoscopy results are summarized in Table 13. A significantly greater proportion of patients in both the XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily treatment groups achieved the following endpoints at Week 52 as compared to placebo: remission, improvement of endoscopic appearance of the mucosa, normalization of endoscopic appearance of the mucosa, maintenance of clinical response, remission among patients in remission at baseline, and sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline. (See Table 13.)
Click on icon to see table/diagram/imageIn both subgroups of patients with or without prior TNF inhibitor failure, a greater proportion of patients treated with either XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily achieved the following endpoints at Week 52 of Study UC-III as compared to placebo: remission, improvement of endoscopic appearance of the mucosa, or sustained corticosteroid-free remission at both Week 24 and Week 52 among patients in remission at baseline (Table 14). This treatment difference from placebo was similar between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily in the subgroup of patients without prior TNF inhibitor failure. In the subgroup of patients with prior TNF inhibitor failure, the observed treatment difference from placebo was numerically greater for XELJANZ 10 mg twice daily than XELJANZ 5 mg twice daily by 9.7 to 16.7 percentage points across the primary and key secondary endpoints. (See Table 14.)
Click on icon to see table/diagram/imageThe proportion of patients meeting treatment failure criteria over time in maintenance Study UC-III is shown in Figure 6. Treatment failure was defined as an increase in Mayo score of at least 3 points from the baseline of the maintenance study, accompanied by an increase in rectal bleeding subscore by at least 1 point, and an increase of endoscopic subscore of at least 1 point yielding an absolute endoscopic subscore of at least 2 after a minimum treatment of 8 weeks in the study. The centrally read endoscopic subscore was used to determine treatment failure.
The proportion of patients in both XELJANZ groups who had treatment failure was lower compared to placebo at each time point as early as Week 8, the first time point where treatment failure was assessed. (See Figure 6.)
Click on icon to see table/diagram/imageOther Health-Related Outcomes: General health status was assessed by the Short Form health survey (SF 36). In induction Study UC-I and Study UC-II, patients receiving XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS) and mental component summary (MCS) scores, and in all 8 domains of the SF 36. In the maintenance Study UC-III, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater maintenance of improvement compared to placebo in PCS, and MCS scores and in all 8 domains of the SF-36 at Week 24 and Week 52.
Disease-specific health status was assessed with the Inflammatory Bowel Disease Questionnaire (IBDQ) in ulcerative colitis patients. In induction Study UC-I and Study UC-II, patients receiving XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in the total and all 4 domain scores of the IBDQ at Week 8. In the maintenance Study UC-III, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater maintenance of improvement compared to placebo in the total and all 4 domain scores of the IBDQ at Week 24 and Week 52.
Health state utilities were assessed with the EuroQoL 5-Dimension (EQ-5D) questionnaire inulcerative colitis patients. In induction Study UC-I, patients receiving XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in the utility score at Week 8; in induction Study UC-II, patients receiving XELJANZ 10 mg twice daily did not demonstrate greater improvement from baseline compared to placebo in the utility score at Week 8. In the maintenance Study UC-III, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater maintenance of improvement from baseline compared to placebo in the EQ-5D health state utility scores at Week 24 and Week 52.
Work Productivity and Activity Impairment (WPAI) were assessed with the WPAI-Ulcerative Colitis (WPAI-UC) questionnaire in ulcerative colitis patients. In induction Study UC-I, patients receiving XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in the presenteeism, work productivity loss and non-work activity impairment domains, but not the absenteeism domain at Week 8; in induction Study UC-II, patients receiving XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in the non-work activity impairment domain, but not the absenteeism, presenteeism, or work productivity loss domains at Week 8. In the maintenance Study UC-III, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater maintenance of improvement from baseline compared to placebo in the presenteeism and non-work activity impairment domain scores, but not the absenteeism or work productivity loss domains at Week 52.
Open-label Extension Study (Study UC-IV): In Study UC-IV, a total of 944 patients were enrolled and assigned to either XELJANZ 5 mg twice daily (for patients in remission at baseline of Study UC-IV) or XELJANZ 10 mg twice daily (for all other patients entering Study UC-IV).
Among the patients who participated in Study UC-IV, 295 who received XELJANZ 10 mg twice daily and did not achieve clinical response in 1 of the induction studies (Study UC-I or Study UC-II) and then continued to receive XELJANZ 10 mg twice daily in Study UC-IV. After an additional 8 weeks of treatment with XELJANZ 10 mg twice daily (16 weeks total), 154/293 (52.6%) patients achieved clinical response and 42/293 (14.3%) patients achieved remission.
In addition, 58 patients received XELJANZ 10 mg twice daily in Study UC-I or Study UC-II and achieved clinical response, had their dose reduced to XELJANZ 5 mg twice daily in Study UC-III and experienced treatment failure, and then had their dose increased to XELJANZ 10 mg twice daily in Study UC-IV. After 2 months on XELJANZ 10 mg twice daily in Study UC-IV, remission and mucosal healing were achieved in 20/58 (34.5%) and 24/58 (41.4%) patients, respectively. At Month 12 in Study UC-IV, 25/48 (52.1%) and 29/48 (60.4%) of these patients achieved remission and mucosal healing, respectively. Further, there were 65 patients enrolled for at least 1 year before the data cut-off date of 08 July 2016 in Study UC-IV after achieving remission at the end of Study UC-III while receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily. At Month 12 of Study UC-IV, 48/65 (73.8%) of these patients remained in remission while receiving XELJANZ 5 mg twice daily.
Polyarticular Course Juvenile Idiopathic Arthritis: The tofacitinib clinical development program for pcJIA was designed to evaluate the safety and efficacy of tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily for patients aged 2 years to <18 years. Patients with pcJIA (rheumatoid factor positive or negative polyarthritis, extended oligoarthritis, or systemic JIA with active arthritis and no current systemic symptoms), juvenile PsA, and enthesitis-related arthritis (ERA) were included in the study. There were 142 patients with pcJIA, 15 with juvenile PsA, and 16 with ERA randomized into the double-blind phase of the study. Patients were allowed to be on MTX, but not required to. The Phase 3 program consisted of one completed Phase 3 trial (Study pcJIA-I [A3921104]) and one ongoing long-term extension (LTE) (A3921145) trial.
All eligible patients in Study pcJIA-I received open-label tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily for 18 weeks (run-in phase); patients who achieved at least a JIA ACR30 response at the end of the open-label phase were randomized (1:1) to either active tofacitinib 5 mg film-coated tablets or tofacitinib oral solution, or placebo in the 26-week double-blind, placebo-controlled phase. Patients who did not achieve a JIA ACR30 response at the end of the open-label run-in phase or experienced a single episode of disease flare at any time were discontinued from the study. A total of 225 patients were enrolled in the open-label run-in phase. Of these, 173 (76.9%) patients were eligible to be randomized into the double-blind phase to either active tofacitinib 5 mg film-coated tablets or tofacitinib oral solution weight-based equivalent twice daily (n=88) or placebo (n=85).
Signs and Symptoms: A significantly smaller proportion of patients in Study pcJIA-I treated with tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily flared at Week 44 compared with patients treated with placebo. A significantly greater proportion of patients treated with tofacitinib 5 mg film-coated tablets or tofacitinib oral solution achieved JIA ACR30, 50, and 70 responses compared to patients treated with placebo at Week 44 (Table 16).
The occurrence of disease flare and JIA ACR30, 50, and 70 response rates for patients with juvenile PsA and ERA were consistent with those of the overall pcJIA results.
The occurrence of disease flare and the percentage of JIA ACR50 responders in the double-blind phase of Study pcJIA-I is shown in Figure 7 and 8, respectively. The occurrence of disease flare over time was significantly less for tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily compared to placebo beginning at Week 24 and continuing through Week 44. The JIA ACR50 responses over time were significantly greater for tofacitinib 5 mg film-coated tablets or tofacitinib oral solution compared to placebo beginning at Week 24 and continuing through Week 44.
In Study pcJIA-I, the least squares (LS) mean change from baseline (Week 18) in Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS-27 CRP) was significantly lower from Week 20 through Week 44 (Table 15) in the tofacitinib 5 mg film coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily compared to placebo (Figure 9).
In Study pcJIA-I at Week 2 of the open-label run-in phase, the JIA ACR30 response was 45.11% and the mean (standard error) change from open-label run-in baseline in JADAS-27 CRP score was -6.35 (0.40). (See Table 15.)
Click on icon to see table/diagram/imageThe occurrence of disease flare by visit for Study pcJIA-I is shown in Figure 7. (See Figure 7.)
Click on icon to see table/diagram/imageThe ACR50 response rates by visit for Study pcJIA-I is shown in Figure 8. (See Figure 8.)
Click on icon to see table/diagram/imageThe LS mean change from double-blind baseline in JADAS-27 CRP for Study pcJIA-I is shown in Figure 9. (See Figure 9.)
Click on icon to see table/diagram/imageIn the double-blind phase, each of the components of the JIA ACR response showed greater improvement from the open-label baseline (Day 1) through Week 44 for patients treated with tofacitinib oral solution dosed as 5 mg twice daily or weight-based equivalent twice daily compared with those receiving placebo in Study pcJIA-I (Table 16). (See Table 16.)
Click on icon to see table/diagram/imagePhysical function and health-related quality of life: Changes in physical function in Study pcJIA-I were measured by the CHAQ Disability Index. The mean change from the double-blind baseline in CHAQ-Disability Index was significantly lower in the tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily compared to placebo at Week 44 (Table 16).
The LS mean change from double-blind baseline in CHAQ Disability Index for Study pcJIA-I is shown in Figure 10. (See Figure 10.)
Click on icon to see table/diagram/imagePharmacokinetics: The PK profile of XELJANZ is characterized by rapid absorption (peak plasma concentrations are reached within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases in systemic exposure. Steady-state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.
Absorption and Distribution: Tofacitinib is well-absorbed, with an oral bioavailability of 74% following administration of XELJANZ. Co-administration of XELJANZ with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, tofacitinib was administered without regard to meal.
After intravenous administration, the volume of distribution is 87 L. Approximately 40% of circulating tofacitinib is bound to proteins. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
Metabolism and Elimination: Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged drug, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. All metabolites have been observed in animal species and are predicted to have ≤10% of the potency of tofacitinib for JAK1/3 inhibition. No evidence of stereo conversion in human samples was detected. The pharmacologic activity of tofacitinib is attributed to the parent molecule. In vitro, tofacitinib is a substrate for multidrug resistance (MDR) 1, but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1/1B3, or organic cationic transporter (OCT) 1/2, and is not an inhibitor of MDR1, OAT P1B1/1B3, OCT2, organic anion transporter (OAT) 1/3, or multidrug resistance-associated protein (MRP) at clinically meaningful concentrations.
Pharmacokinetic data and dosing recommendations for special populations and drug interactions are provided in Figure 11.
Modifications required for special populations are described in Dosage & Administration.
Pharmacokinetics in RA Patients: Population PK analysis in rheumatoid arthritis patients indicated that systemic exposure (AUC) of tofacitinib in the extremes of body weight (40 kg, 140 kg) were similar to that of a 70 kg patient. Elderly patients 80 years of age were estimated to have <5% higher AUC relative to the mean age of 55 years. Women were estimated to have 7% lower AUC compared to men. The available data have also shown that there are no major differences in tofacitinib AUC between White, Black and Asian patients. An approximate linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (percentage coefficient of variation) in AUC of XELJANZ is estimated to be approximately 27%.
Pharmacokinetics in Patients with Active Psoriatic Arthritis: Population PK analysis in patients with active psoriatic arthritis indicated that systemic exposure (AUC) of tofacitinib in the extremes of body weight [61 kg, 109 kg (10th and 90th percentile in population dataset)] were similar to that of a 83.3 kg patient. Elderly patients 80 years of age were estimated to have 10% higher AUC relative to the mean age of 50 years. Women were estimated to have 5% lower AUC compared to men. The available data have also shown that there are no major differences in tofacitinib AUC between White, Black and Asian patients. The between-subject variability (percentage coefficient of variation) in AUC of XELJANZ is estimated to be approximately 32%.
Pharmacokinetics in Patients with Active Ankylosing Spondylitis: Population PK analysis in patients with active ankylosing spondylitis indicated that there were no clinically relevant differences in tofacitinib exposure, based on age, weight, gender, and race. Elderly patients 64 years of age were estimated to have 11% lower clearance relative to patients at the median age of 40 years. Women were estimated to have 2% higher clearance compared to men and Asian patients had a 10% lower clearance compared to non-Asian patients. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 28% in patients with active ankylosing spondylitis.
Pharmacokinetics in Patients with Active Ulcerative Colitis: Population PK analysis in ulcerative colitis patients indicated that there were no clinically relevant differences in tofacitinib exposure (AUC), based on age, weight, gender, and race. Exposure in women was 15% higher than in men, and Asian patients had 7.3% higher exposure than non-Asian. Volume of distribution increased with body weight resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 23% and 25% at the 5 mg twice daily dose and 10 mg twice daily dose, respectively, in ulcerative colitis patients.
Pharmacokinetics in pcJIA Patients: Population PK analysis based on results from both tofacitinib 5 mg film-coated tablets twice daily and tofacitinib oral solution weight-based equivalent twice daily indicated that tofacitinib clearance and volume of distribution both decreased with decreasing body weight in pcJIA patients. The available data indicated that there were no clinically relevant differences in tofacitinib exposure (AUC), based on age, race, gender, patient type or baseline disease severity. The between-subject variability (% coefficient of variation) in (AUC) was estimated to be approximately 24%.
Renal Impairment: Patients with mild, moderate, and severe renal impairment had 37%, 43% and 123% higher AUC, respectively, compared with healthy patients (see Dosage & Administration). In patients with end-stage renal disease, the contribution of dialysis to the total clearance of tofacitinib was relatively small.
Hepatic Impairment: Patients with mild and moderate hepatic impairment had 3%, and 65% higher AUC, respectively, compared with healthy patients. Patients with severe hepatic impairment were not studied (see Dosage & Administration).
Pediatric Population: The pharmacokinetics, safety and efficacy of tofacitinib in pediatric patients have not been established, with the exception of pcJIA.
The pharmacokinetics, safety and efficacy of XELJANZ has been evaluated in pcJIA patients 2 years to <18 years of age. (See Figure 11.)
Click on icon to see table/diagram/imageToxicology: Preclinical safety data: In non-clinical studies, effects were observed on the immune and hematopoietic systems that were attributed to the pharmacological properties (JAK inhibition) of tofacitinib. Secondary effects from immunosuppression, such as bacterial and viral infections and lymphoma were observed at clinically relevant doses. Other findings at doses well above human exposures included effects on the liver, lung and gastrointestinal systems.
Lymphoma was observed in 3 of 8 adult and 0 of 14 juvenile monkeys dosed with tofacitinib at 5 mg/kg twice daily. The no observed adverse effect level (NOAEL) for the lymphomas was 1 mg/kg twice daily. The unbound AUC at 1 mg/kg twice daily was 341 ng·h/mL, which is approximately half of the unbound AUC at 10 mg twice daily and similar to the unbound AUC at 5 mg twice daily in humans.
Tofacitinib is not mutagenic or genotoxic based on the results of a series of in vitro and in vivo tests for gene mutations and chromosomal aberrations.
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib was not carcinogenic in mice up to a high dose of 200 mg/kg/day (unbound drug AUC of ~19-fold the human AUC at 10 mg twice daily). Benign Leydig cell tumors were observed in rats: benign Leydig cell tumors in rats are not associated with a risk of Leydig cell tumors in humans. Hibernomas (malignancy of brown adipose tissue) were observed in female rats at doses ≥30 mg/kg/day (unbound drug AUC of ~41-fold the human AUC at 10 mg twice daily). Benign thymomas were observed in female rats dosed only at the 100 reduced to 75 mg/kg/day dose (unbound drug AUC of ~94-fold the human AUC at 10 mg twice daily).
Tofacitinib was shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility, parturition, and peri-/post-natal development. Tofacitinib had no effects on male fertility, sperm motility, or sperm concentration. Tofacitinib was secreted in milk of lactating rats. In studies conducted in juvenile rats and monkeys tofacitinib-related effects on the immune system were similar to those in adult animals. There were no tofacitinib-related effects on reproductive system or bone development in males or females.
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