Across the phase III studies, 100 Australian patients with RA were randomized to receive tofacitinib 5 mg BID (n = 33), tofacitinib 10 mg BID (n = 47), placebo (n = 13), or adalimumab 40 mg Q2W (n = 7). The demographic and baseline disease characteristics are reported in Table 1. The majority of patients in the Australian population were female, with established RA (mean disease duration > 6 years in all treatment groups) and a high level of baseline disease activity [mean DAS28-4(ESR) ≥ 5.9 in all treatment groups]. The majority of patients in each treatment group were Caucasian (≥ 85.7%). Patients in the tofacitinib 5 mg BID group had the longest mean disease duration (12.1 years); this was almost twice that of patients in the adalimumab group, though the smaller sample size must be taken into consideration.
The LTE study involved 99 Australian patients, with tofacitinib exposure of 322.5 patient-years. Two patients received an average TDD of tofacitinib 5 mg BID; one discontinued treatment after month 3 due to insufficient clinical response. Data from the LTE study for patients receiving tofacitinib 5 and 10 mg BID are presented together in these analyses, unless otherwise indicated.
In the phase III studies, patients receiving tofacitinib 5 and 10 mg BID had numerically greater ACR20 response rates than those receiving placebo at months 1 and 3; ACR20 response rates increased to month 12 (Fig. 1a). The ACR50 response rates in the treatment groups also improved over time to month 12 (Fig. 1b). ACR70 response rates were either zero or low for all groups prior to month 3, and increased over time until month 12 (Fig. 1c). By month 12, all placebo-treated patients had advanced to tofacitinib and achieved ACR20, ACR50, and ACR70 response rates similar to those of the tofacitinib-treated patients.
At month 12, a numerically higher proportion of patients who had received placebo and advanced to tofacitinib achieved clinical remission [DAS28-4(ESR) < 2.6] and LDA [DAS28-4(ESR) ≤ 3.2], compared with tofacitinib-treated patients (Fig. 1d). Treatment with tofacitinib 5 and 10 mg BID was associated with numerically greater improvement vs. placebo in DAS28-4(ESR) scores at months 1 and 3 (Fig. 1e); however, it must be noted that not all patients had DAS28-4(ESR) scores assessed at month 1. The mean changes from baseline in DAS28-4(ESR) were similar for all groups at months 6 and 12, including the placebo-treated patients, once they had been advanced to tofacitinib; the numerically higher rates of remission and LDA in these patients may be due to low patient numbers compared with tofacitinib-treated patients.
HAQ-DI scores decreased from baseline through month 12, indicating improvement with active treatment (Fig. 1f). After month 6, improvement in HAQ-DI was also observed in patients who had advanced from placebo to tofacitinib.
Adalimumab resulted in similar ACR20 and lower ACR50 response rates vs. tofacitinib at Month 12; none of the seven patients receiving adalimumab achieved an ACR70 response (Fig. 1a–c). Additionally, although similar changes from baseline in DAS28-4(ESR) and HAQ-DI were observed with tofacitinib and adalimumab at month 12 (Fig. 1e–f), a numerically lower percentage of adalimumab-treated patients achieved remission and LDA vs. patients receiving tofacitinib (Fig. 1d).
Efficacy improvements with tofacitinib were sustained for up to 60 months of treatment in the LTE study (Fig. S1). In tofacitinib-treated patients, ACR response rates generally increased between month 1 and 60 (Fig. S1a). Mean improvements from baseline in DAS28-4(ESR) scores remained stable through month 60 in patients receiving tofacitinib (Fig. S1b). Mean HAQ-DI scores also improved from baseline, although a slight decrease in the change from baseline was observed at months 48 and 54 before increasing again at month 60 (Fig. S1c).
Analysis of PROs in the phase III Australian subpopulation showed that treatment with tofacitinib 5 and 10 mg BID improved SF-36 scores, PtGA, pain, fatigue, and sleep disturbance. Consistent increases from baseline, indicating improvement, were seen in all eight domains of the SF-36 at month 3 with tofacitinib 5 and 10 mg BID (Fig. 2a). SF-36 mean PCS and MCS improved from baseline to month 12 in patients treated with tofacitinib 5 and 10 mg BID (Fig. 2b–c). There was a slight increase in PCS and MCS at month 1 in patients receiving placebo, but this was not sustained to month 3. Improvements from baseline PCS and MCS were observed at month 6 after patients switched from placebo to tofacitinib at either month 3 or 6. Patients receiving adalimumab achieved greater changes from baseline in SF-36 social function, vitality, bodily pain, and general health domains at month 3, and similar changes from baseline in PCS and MCS scores at month 12 compared with patients receiving tofacitinib (Fig. 2).
In the tofacitinib 5 and 10 mg BID treatment groups, improvements in PtGA, pain, fatigue, and sleep disturbance scores were observed until month 12 (Figs. S2a–d). Similar improvements were observed in the placebo-treated patients after month 6 upon advancement to tofacitinib.
The seven patients receiving adalimumab appeared to experience similar improvements from baseline compared with tofacitinib through month 12 in all PROs except PtGA (Figs. S2a–d).
Furthermore, patients receiving tofacitinib 5 or 10 mg BID were more likely to achieve clinically meaningful improvements for PtGA, pain, SF-36 PCS, and FACIT-F at month 1 and 3 (Table S1) vs. patients receiving placebo, as more patients reported improvements that were greater than the MCID.
During months 0–3 of the phase III studies, the incidence of AEs was similar between the tofacitinib and placebo groups. The incidence of AEs in patients receiving tofacitinib 5 and 10 mg BID was 78.8 and 72.3%, respectively, at months 0–3, 51.4 and 48.1%, respectively, at months 3–6, and 55.9 and 46.3%, respectively, post-month 6 (Table 2). SAEs and discontinuations due to AEs occurred more frequently with tofacitinib vs. placebo until month 6 (Table 2).
Of the seven adalimumab-treated patients, four reported AEs at months 0–3, two at months 3–6, and two post-month 6. One patient reported an SAE at months 3–6. None of the patients receiving adalimumab discontinued due to AEs during the phase 3 studies (Table 2).
During the LTE study, SAEs were reported in 50 (50.5%) tofacitinib-treated patients (Table 2). Overall, 53 (53.5%) patients discontinued the study; 27 discontinued due to study drug-related AEs, while eight discontinued due to insufficient clinical response, including one patient receiving tofacitinib 5 mg BID (data not shown).
Upper respiratory tract infection was the most frequently occurring AE in patients receiving tofacitinib 5 and 10 mg BID during months 0–3 (12.1 and 8.5%, respectively), months 3–6 (5.4 and 9.3%, respectively), and post-month 6 (8.8 and 18.5%, respectively) of the phase III studies (Table 3). Upper respiratory tract infection was also the most commonly reported treatment-emergent AE during the LTE study (45.5%) (Table 3).
The AEs of special interest reported during the LTE study are listed in Table 3. The most common AE of special interest was NMSC, followed by SIEs; these were reported in 22 [incidence rate: 7.8 (95% confidence interval (CI) 4.9, 11.9)] and 21 [incidence rate: 6.6 (95% CI 4.1, 10.0)] patients, respectively. HZ occurred in 18 (18.2%) patients; three cases were serious and patients permanently discontinued treatment, and all except one non-serious case were resolved. Malignancies and opportunistic infections were each reported in four (4.0%) patients during the LTE study (Table 3).
Selected laboratory parameters assessed during the LTE study are summarized in Fig. 3 and Table S2. Hemoglobin levels slightly decreased from baseline to month 30 with tofacitinib treatment, subsequently increased to month 48, then decreased to month 60 (Fig. 3a). Mean ALC decreased through month 60 (Fig. 3b). The mean ANC somewhat decreased at month 1 and fluctuated throughout the LTE study, but by month 60 had returned to a similar level as month 1 (Fig. 3c). Mean creatinine levels increased from baseline at month 1, and also fluctuated before returning to a level similar to month 1 by month 60 (Fig. 3d). HDL cholesterol levels increased from baseline at month 1 and remained stable, but LDL cholesterol levels initially increased to month 24, decreased at month 30, then increased at month 36 before decreasing to below the baseline value at month 60 (Fig. 3e). A summary of abnormal laboratory observations meeting protocol for monitoring or discontinuation is provided in Table S2. The proportions of patients receiving tofacitinib who had confirmed decreases in hemoglobin, neutrophil count, and lymphocyte count, and increases in AST and/or ALT levels, and serum creatinine, was ≤ 5.1% for each measurement.