Chan, Gary

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program. Methods Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. Results Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years’ treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors. Conclusions For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Abstract Background and Aims Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes. Methods Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event]. Results In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23–7.00] for placebo and 1.35 [0.16–4.87] and 0.64 [0.02–3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02–5.42], 2.05 [0.42–6.00], and 6.64 [3.19–12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24–2.27], 3.48 [2.79–4.30], and 0.15 [0.04–0.38], respectively. No SIs resulted in death. Conclusions During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were demonstrated in patients with moderate to severe UC in 3 Phase 3 studies.1 Here, we present data from an ongoing, open-label, long-term extension (OLE) study.2 Methods We present updated safety and efficacy data from the OLE study (OCTAVE Open, NCT01470612; as of May 2019, database not locked). Eligible patients included non-responders (Week 8 data) in OCTAVE Induction 1 and 2 (NCT01465763; NCT01458951) and completers (Week 52 data) or treatment failures (early-termination data) in OCTAVE Sustain (NCT01458574). Patients in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding [RB] subscore 0) at Week 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID); all others received 10 mg BID. Induction non-responders without clinical response (≥3-point and ≥30% decrease from induction study baseline total Mayo score, plus ≥1-point RB subscore decrease or absolute RB subscore ≤1) at Month 2 of the OLE study were withdrawn. Incidence rates (IRs) for adverse events (AEs) of special interest were calculated (no. of unique patients with events per 100 patient-years). Efficacy endpoints were derived from Mayo score (local read) with non-responder and last observation carried forward imputation (NRI-LOCF) [a]. Results Of 944 patients who received ≥1 dose of tofacitinib, 769 (81.5%) received 10 mg BID (median duration [range]: 5 mg BID 1170 [36–2066]; 10 mg BID 668 [1–2159] days). In total, 338 (35.8%) and 93 (9.9%) patients discontinued due to insufficient clinical response and AEs (excl. worsening UC), respectively. IRs (95% confidence interval) in the Tofacitinib. All group were: deaths 0.18 (0.05, 0.47); serious infections 1.57 (1.08, 2.19); herpes zoster (non-serious and serious) 3.27 (2.54, 4.14); major adverse cardiovascular events 0.14 (0.03, 0.40); malignancies excl. non-melanoma skin cancer (NMSC) 0.92 (0.56, 1.42); NMSC 0.74 (0.43, 1.21); deep vein thrombosis 0.05 (0.00, 0.25); pulmonary embolism 0.18 (0.05, 0.47) (Table). At Month 36 (NRI-LOCF), 58.9% (n = 103) and 33.5% (n = 257) were in remission, 64.6% (n = 113) and 37.0% (n = 284) had mucosal healing (Mayo endoscopic subscore of 0 or 1) [b] and 66.9% (n = 117) and 40.2% (n = 309) showed clinical response, in the 5 and 10 mg BID groups, respectively. Conclusion Incidence of AEs remained generally consistent in patients with moderate to severe UC in the OLE study compared with a previous analysis.2 Data continue to support long-term efficacy with tofacitinib up to 36 months beyond Week 52 of OCTAVE Sustain. References

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety in patients (pts) with UC was evaluated in an 8-week induction Phase (P) 2 study (NCT00787202), 1 2 8-week induction P3 studies (OCTAVE Induction 1 & 2; NCT01465763 & NCT01458951), 2 a 52-week maintenance P3 study (NCT01458574), and an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612). 3 We present updated infections data (Sep 2018) from the tofacitinib UC clinical program. 4,5 METHODS: Pts receiving placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as Induction (P2 & P3, n = 1220), Maintenance (P3, N = 592), and Overall (pts in P2, P3 & OLE receiving tofacitinib 5 or 10 mg BID, N = 1157 [Sep 2018]) Cohorts. Proportions and incidence rates (IRs; pts with events per 100 pt-years [PY] of exposure) were evaluated for infections of special interest (incl. serious infections [SIs], opportunistic infections [OIs; independently adjudicated], and herpes zoster [HZ]). RESULTS: A total of 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID (83% predominantly 10 mg BID [avg. daily dose ≥15 mg]), with 2403.6 PY of exposure (median 623 days, up to 6.1 years of treatment). The Table 1 shows infection IRs by Cohort. In the Overall Cohort, nasopharyngitis was the most frequent infection. For SIs, the Overall Cohort “Tofacitinib All” IR (1.75 [95% CI 1.27, 2.36]) was similar to the Maintenance Cohort IRs for tofacitinib 5 and 10 mg BID. No SIs resulted in death. OIs were infrequent (28 pts) and most were HZ (24 pts; IR 0.99 [95% CI 0.63, 1.47]), mostly cutaneous. Not all HZ events were OIs; 83 pts overall had HZ events (IR 3.57 [95% CI 2.84, 4.43]; 6 serious). CONCLUSION: In induction, SIs and OIs occurred with tofacitinib but not with placebo. Overall, SIs were generally infrequent and Overall Cohort IRs did not suggest increased risk with longer tofacitinib treatment vs the Maintenance Cohort. Non-HZ OIs were rare. SI incidence was similar in the UC and rheumatoid arthritis programs (incl. increased HZ risk) 6 and to other UC therapies incl. biologics. 7

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety and efficacy were demonstrated in patients (pts) with moderate to severe UC in 3 Phase 3 studies, 1 and are being evaluated in an ongoing, open-label, long-term extension (OLE) study. 2 METHODS: We present updated safety and efficacy data from the OCTAVE Open OLE study (NCT01470612; Sep 2018; database not locked) 2 in completers/treatment failures in OCTAVE Sustain (NCT01458574) or non-responders in OCTAVE Induction 1/2 (NCT01465763/NCT01458951). Week (Wk) 8 data (OCTAVE Induction 1/2) and Wk 52 (completers) or early-termination data (OCTAVE Sustain) determined eligibility. Pts in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding subscore 0) at Wk 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID) in the OLE study; all others received 10 mg BID. At Month 2, all pts had endoscopy, and induction non-responders with no clinical response were withdrawn. Incidence rates (IRs; unique pts with events per 100 pt-years [PY]) for adverse events (AEs) of special interest were calculated. Efficacy endpoints were derived from Mayo score (local read). RESULTS: Of 944 pts receiving ≥1 tofacitinib dose (for up to 5.5 years), 175 (18.5%) and 769 (81.5%) received 5 and 10 mg BID, respectively (454 and 1550 PY, respectively). 337 (35.7%) pts discontinued due to insufficient clinical response and 78 (8.3%) due to AEs excl. worsening UC. The most frequent AE class was infections and infestations (52.1%). The most frequent AEs were nasopharyngitis (20.3%) and worsening UC (19.5%). IRs (95% CI) for “Tofacitinib All” were: serious infections 1.61 (1.10, 2.27); herpes zoster (all) 3.35 (2.58, 4.27); major adverse cardiovascular events 0.15 (0.03, 0.44); malignancies excl. non-melanoma skin cancer (NMSC) 0.85 (0.50, 1.36); and NMSC 0.81 (0.46, 1.32), with no clustering of malignancy type. Table 1 shows AEs and IRs by dose. No new safety risks were identified. Table 2 shows efficacy data at Month 36. CONCLUSION: In pts with UC in the OLE study, no new safety risks emerged at 5.5 years vs earlier OLE analyses 2 or with tofacitinib in rheumatoid arthritis. Efficacy data continue to support long-term efficacy of tofacitinib 5 or 10 mg BID up to 36 months beyond OCTAVE Sustain.