Background/Purpose: Tofacitinib is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy for RA. Phase (P) 3 studies demonstrated tofacitinib is effective and has a manageable safety profile at both 5 and 10 mg twice daily (BID) doses. These post‑hoc analyses of pooled P3 and long-term extension (LTE) data assessed whether there are relative differences in efficacy or safety between the two doses.

Methods:

Data from patients (pts) receiving tofacitinib 5 or 10 mg BID were pooled from five randomized P3 and two open-label LTE studies. Pooling was justified by similarity of demographic and baseline (BL) disease characteristics of pts across the studies. For efficacy comparisons, pooled P3 data were assessed for signs and symptoms (rates of ACR response, rates of DAS28-4[ESR] (DAS) ≤3.2 and <2.6), physical function (rates of HAQ-DI improvement ≥0.3), and fatigue (rates of FACIT improvement ≥4) (all at Month 3). For safety comparisons, pooled P3 and LTE incidence rates (IR) (events/100 pt-y) were assessed for all-cause mortality, serious infection events (SIE), malignancies (excluding non-melanoma skin cancer), lung cancers, major adverse cardiovascular events, GI perforations and herpes zoster. Results were expressed as probability (proportion of responders for efficacy) or risk (IR for safety) ratios, respectively, for 10 mg BID divided by that of 5 mg BID, with 95% confidence intervals (CIs).

Results: 

In the efficacy analysis, the robust group sizes (approximately 1100 pts each) allowed demonstration of statistical separation (95% CIs excluding 1) of 10 mg BID from 5 mg BID for each of the efficacy endpoints except fatigue. Point estimates for the 10 mg BID / 5 mg BID ratios were between 1.11 and 1.15 for ACR20 responses, ACR50 responses and HAQ-DI improvement ≥0.3, and between 1.30 and 1.43 for ACR70 responses and rates of DAS28 ≤3.2 and <2.6, indicating a greater likelihood of achieving the more stringent outcomes with the 10 mg BID dose compared with 5 mg BID. In the safety analyses, all the CIs for important safety events included 1, indicating similar rates between doses, with the exception of increases in SIEs for 10 mg BID in LTE (risk ratio 1.74 [95% CI 1.24, 2.45]). In contrast to LTE, SIE risk ratio was 0.92 (95% CI 0.55, 1.56) in P3. Malignancy risk ratios were 1.59 (95% CI 0.52, 4.86) in P3 and 1.17 (95% CI 0.67, 2.05) in LTE. As patients from P2 received 5 mg BID in LTE, and pts from P3 received 10 mg BID in LTE, there were more pts receiving 10 (N=2415) compared with 5 mg BID (N=1370) in LTE but the exposure was greater for 5 than 10 mg BID (2700 vs 1700 pt-y).

Conclusion: Both doses of tofacitinib, 5 and 10 mg BID, are efficacious across multiple domains of efficacy. Pooled analyses show statistical separation of 10 mg BID vs 5 mg BID on most efficacy parameters except fatigue. Event rates for safety are generally similar between the two doses but differences were noted in SIE rates in LTE, favoring 5 mg BID. Importantly, event rates for the tofacitinib 5 and 10 mg BID dose groups in both the P3 and LTE studies are well within the ranges observed with biologic therapies approved for treatment of RA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-an-oral-janus-kinase-inhibitor-analyses-of-efficacy-and-safety-of-10-versus-5mg-twice-daily-in-a-pooled-phase-3-and-long-term-extension-rheumatoid-arthritis-population/