Lawendy, Nervin

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.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Safety and efficacy of tofacitinib were demonstrated in Phase (P) 2/3 induction studies (NCT00787202; NCT01465763; NCT01458951), a 52-week, P3 maintenance study (NCT01458574), and are being further investigated in an ongoing, open-label, long-term extension (OLE) study (NCT01470612). This analysis assessed age as a risk factor for adverse events (AEs) in the tofacitinib UC clinical program. METHODS: Analyses of AEs were performed for 2 cohorts: the Maintenance Cohort (patients who received placebo or tofacitinib 5 or 10 mg twice daily in the maintenance study) and the Overall Cohort (all tofacitinib-treated patients in the P2/P3/OLE studies [as of December 2016]), stratified by age (≥65 years vs <65 years). AEs of special interest included serious infections (SIs), opportunistic infections (OIs), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE), and gastrointestinal perforations. Risk factors (based on baseline characteristics) for SIs, OIs, HZ, and NMSC in the Overall Cohort were evaluated using multivariate Cox proportional regression models. RESULTS: AEs occurred in 75.3% (placebo) and 75.9% (tofacitinib) of patients in the Maintenance Cohort, and 82.1% in the Overall Cohort (in which 83.9% received predominantly tofacitinib 10 mg twice daily). Most patients (Maintenance Cohort: 180/198 [90.9%] and 364/394 [92.4%] receiving placebo and tofacitinib, respectively; Overall Cohort: 1,080/1,157 [93.3%]) were aged <65 years. In both the placebo and tofacitinib groups of the Maintenance Cohort, rates of AEs, serious AEs, severe AEs, and discontinuations due to AEs were numerically higher in patients aged ≥65 years (placebo: 83.3%, 11.1%, 11.1%, and 22.2%; tofacitinib: 80.0%, 16.7%, 10.0%, and 16.7%) vs <65 years (placebo: 74.4%, 6.1%, 9.4%, and 18.3%; tofacitinib: 75.5%, 4.4%, 7.1%, and 8.8%). AEs of special interest were generally infrequent in both the placebo and tofacitinib groups of the Maintenance Cohort. In the Overall Cohort, AE, serious AE, and severe AE rates were numerically higher in patients aged ≥65 years (88.3%, 19.5%, and 15.6%) vs <65 years (81.7%, 14.3%, and 12.2%). OI, HZ, malignancies (excluding NMSC), NMSC, and MACE rates were numerically higher in patients aged ≥65 years (3.9%, 14.3%, 2.6%, 5.3%, and 2.6%) vs <65 years (1.7%, 5.0%, 0.6%, 0.7%, and 0.2%); SI and gastrointestinal perforation rates were similar between age groups (≥65 years: 2.6% and 0.0%; <65 years: 2.9% and 0.4%). In multivariate modeling in the Overall Cohort, increasing age (every 10 years) was associated with increased risk of OIs (hazard ratio [95% confidence interval] 1.54 [1.15, 2.08]) and HZ (1.58 [1.34, 1.87]), but not SIs or NMSC (univariate modeling: 1.0 [0.78, 1.27] and 2.31 [1.46, 3.66]). CONCLUSION(S): In the tofacitinib UC program, AE rates were higher among patients aged ≥65 years vs those aged <65 years, regardless of whether they received tofacitinib or placebo. In multivariate analyses, older age was associated with increased OI and HZ risk. Although this is consistent with the general population, due to the small number of patients aged ≥65 years (<10% of the total), these findings should be interpreted with caution.