Tofacitinib Ulcerative Colitis Research Articles

DOP75 Efficacy of tofacitinib dose escalation to 10 mg BID in patients with UC after completing maintenance therapy in remission and losing response: Data from OCTAVE open-label, long-term extension study

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in patients with moderate to severe UC in three Phase 3 studies.1 Here, we investigated outcomes in a subpopulation of the ongoing, open-label, long-term extension study (OLE) (OCTAVE Open; NCT01470612; May 2019; database not locked), including maintenance of remission patients receiving tofacitinib 5 mg twice daily (BID) who were dose-escalated to 10 mg BID due to flare. Methods Analysis included the maintenance remission–dose-escalation subpopulation: patients who achieved remission at Week 52 in OCTAVE Sustain (tofacitinib 5 or 10 mg BID, or placebo), entered OLE (5 mg BID), but were dose-escalated to 10 mg BID due to flare (based on total Mayo score [MS]; local read endoscopy). Remission: total MS ≤2 with no subscore >1, and rectal bleeding (RB) subscore 0. Dose escalation during OLE was permitted if patients experienced a flare, defined as ≥3 increase from maintenance study baseline total MS and ≥1 increase in RB and endoscopic subscore (ES; unless ES=3 at baseline and remained 3) after ≥8 weeks of treatment in OLE. Kaplan–Meier for estimation of time to dose escalation was assessed in all OLE maintenance remission population relative to OLE baseline. Partial MS remission (≤2 with no subscore >1; no ES) assessed at Months (M)3, 6, 9 and 12 post-dose-escalation; mucosal healing (MH; ES ≤1) and remission assessed at M12 post-dose-escalation. Adverse events (AEs) also assessed. Results Of the 944 patients enrolled in OLE, 162 were in remission at baseline and received tofacitinib 5 mg BID, and 41 were dose-escalated to 10 mg BID due to flare (22 had prior TNFi failure). The cumulative proportion of patients with dose escalation was 4.3%, 10.6%, 12.6% and 13.2% at M3, 6, 9 and 12 of OLE, respectively. Partial MS remission was 75.0% at M3, and partial MS remission, MH and remission were 95.0%, 63.6% and 57.6%, respectively, at M12 post-dose escalation (Table). One case each of serious infection, herpes zoster (non-serious; opportunistic infection) and malignancy were reported (see Table). Conclusion For patients with moderate to severe UC who entered OLE in remission, received tofacitinib 5 mg BID but flared and were dose-escalated to 10 mg BID, response was recaptured for most by M3 post-dose-escalation and remission was recaptured in the majority by M12. Safety in this subpopulation was generally consistent with that observed in the overall tofacitinib UC programme.2 Due to the small sample size and open-label nature, results should be interpreted with caution. References

Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses.

Ulcerative colitis (UC) is an inflammatory disease of the colon and rectum. Treatment options include biologics and tofacitinib. We aim to summarize the evidence on efficacy and safety of biologics and tofacitinib in moderate-to-severe UC. PubMed, Embase, Scopus, and the Cochrane Library were systematically searched to identify meta-analyses of randomized controlled trials assessing adalimumab, golimumab, infliximab, vedolizumab, and tofacitinib in UC. Efficacy outcomes included induction and maintenance of clinical response, clinical remission and mucosal healing. Safety outcomes included adverse events and serious adverse events. The overview involved 31 meta-analyses. All four biologics and tofacitinib were superior to placebo regarding efficacy. Indirect comparisons suggested that infliximab may be better than adalimumab and golimumab to induce clinical response and mucosal healing. Safety analyses indicated no increased rates of adverse events, except for infliximab. Biologics and tofacitinib are efficacious and safe for treating UC. These findings can support clinical decision-making.

Venous thromboembolic events in the tofacitinib ulcerative colitis clinical development programme.

SummaryBackgroundTofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC).AimTo report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme.MethodsDVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open‐label, long‐term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts.Results1157 patients (2404 patient‐years’ exposure; ≤ 6.1 years’ tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In maintenance, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate [patients with events/100 patient‐years; 95% CI]: 0.04 [0.00‐0.23]); four had PE (0.16 [0.04‐0.41]); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC.ConclusionsIn this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

705 Tofacitinib for the Treatment of Ulcerative Colitis: An Update on the Analysis of Malignancy Rates From the UC Clinical Program

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of adjudicated malignancies in the UC clinical development program as of Sep 2018. METHODS: Malignancies were evaluated from 4 randomized placebo (PBO)-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], 1 maintenance P3 study [NCT01458574]), and an ongoing, open-label, long-term extension (OLE) study (NCT01470612). 1–3 Three cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study), and Overall (patients [pts] receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, or OLE studies). Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for malignancies (excl. non-melanoma skin cancer [NMSC]) and NMSC. For Overall Cohort analysis, pts were categorized based on the average daily tofacitinib dose: predominant dose (PD) 5 or 10 mg BID. For P3 studies, an independent adjudication committee reviewed all potential malignancies. RESULTS: 1157 pts were evaluated for malignancies (2404 PY of tofacitinib exposure; up to 6.1 years of treatment). Malignancies (excl. NMSC) occurred in 0 Induction Cohort pts, 1 PBO-treated Maintenance Cohort pt, and 17 Overall Cohort pts (IR 0.69; 3 received a PD of tofacitinib 5 mg BID [IR 0.49] and 14 a PD of 10 mg BID [IR 0.75]; Table 1). NMSC occurred in 2 tofacitinib-treated Induction Cohort pts, 4 Maintenance Cohort pts (3 with 10 mg BID-treated pts, IR 1.91; and 1 PBO-treated pt, IR 0.97), and 19 Overall Cohort pts (IR 0.78; 4 had received a PD of 5 mg BID and 15 a PD of 10 mg BID). CONCLUSION: Malignancies (incl. NMSC) were observed with tofacitinib in UC. There was no malignancy type clustering (excl. NMSC). The IR of malignancies (excl. NMSC) reported here is similar to those previously reported for UC [4] – suggesting no treatment duration impact on the IR – and for tofacitinib in pts with rheumatoid arthritis and in pts with UC treated with biologics. 5–7

671 An Update on the Analysis of Non-Melanoma Skin Cancer in the Tofacitinib Ulcerative Colitis Program

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated integrated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical program as of Sep 2018. METHODS: NMSC events were evaluated from 4 randomized, placebo-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], a maintenance P3 study [NCT01458574]), and an ongoing, open-label, long-term extension (OLE) study (NCT01470612). 1–3 Three cohorts were analyzed: Induction (P2/P3 induction studies); Maintenance (P3 maintenance study); Overall (patients [pts] receiving ≥1 dose of tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, or ongoing OLE studies). For P3 studies, a blinded independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. RESULTS: 1124 pts were evaluated for NMSC (P3 studies only), with 2399 PY of tofacitinib exposure and up to 6.1 years of treatment. NMSC occurred in 2 Induction tofacitinib-treated pts, 1 Maintenance placebo-treated pt (IR 0.97), 3 Maintenance 10 mg BID pts (IR 1.91), and 19 Overall Cohort pts (IR 0.78). 10 pts had squamous cell carcinoma (SCC) and 12 pts had basal cell carcinoma (BCC); 3 pts had both SCC and BCC (Table). No NMSC was metastatic or led to discontinuation. The Overall Cohort showed higher IRs for pts aged ≥50 years vs other subgroups and for pts with prior tumor necrosis factor inhibitor treatment, or prior immunosuppressant use vs those without (Table 1). Prior NMSC (hazard ratio [HR] 10.95; 95% CI 3.72, 32.24; P < 0.0001) and age (HR per 10-year increase 2.10; 95% CI 1.41, 3.13; P = 0.0003) were significant risk factors for NMSC. CONCLUSION: NMSC events were infrequent in the tofacitinib UC program, and were more likely to occur in pts with prior NMSC, and with increasing age – known NMSC risk factors. 4 NMSC IRs were similar to those reported for tofacitinib in rheumatoid arthritis 5 and for biologic UC treatments. 6

726 Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates in the Tofacitinib Ulcerative Colitis Clinical Program

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

644 Incidence of Venous Thromboembolic Events in Patients With Ulcerative Colitis Treated With Tofacitinib in the Ulcerative Colitis Clinical Development Program

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). A safety signal for pulmonary embolism (PE) was seen in the tofacitinib 10 mg twice daily (BID) arm of an FDA post-marketing requirement study in rheumatoid arthritis designed to evaluate the long-term risk of major cardiovascular events and malignancy. Patients (pts) eligible for this ongoing, open-label, safety-endpoint-driven study had to be ≥50 yrs of age, have ≥1 cardiovascular risk factor and be on a stable dose of methotrexate. UC is a known risk factor for deep vein thrombosis (DVT) and PE. 1,2 We report the incidence of DVT and PE in the tofacitinib UC clinical program, as of Sep 2018. METHODS: DVT and PE events were evaluated from 4 randomized placebo-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], 1 maintenance P3 study [NCT01458574]), and an ongoing, open-label, long-term extension (OLE) study (NCT01470612). 3–5 Three cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study), and Overall (pts receiving tofacitinib 5 or 10 mg BID in P2, P3, or OLE studies). Incidence rates (unique pts with events per 100 pt-yrs [PY] of exposure) were evaluated. For Overall Cohort analysis, pts were categorized based on the average daily dose of tofacitinib: predominant dose (PD) tofacitinib 5 mg or 10 mg BID. RESULTS: 1157 pts were evaluated for DVT and PE, with 2404 PY of tofacitinib exposure and up to 6.1 yrs of treatment. In the Induction and Maintenance Cohorts, 2 pts had DVT and 2 had PE; all had received placebo in the study (Table 1). In the Overall Cohort, DVT occurred in 1 pt and PE in 4 pts during the OLE study; all pts had received PD of tofacitinib 10 mg BID. All pts with PE and DVT had risk factors for venous thrombosis (Table 1). CONCLUSION: In this post hoc analysis of pts with UC during tofacitinib exposure, 4 pts had PE and 1 pt had DVT, all of which occurred during the OLE study, in pts treated with PD of tofacitinib 10 mg BID (83% of Overall Cohort pts received a PD of tofacitinib 10 mg BID) with risk factors for venous thrombotic events. This analysis is limited by small sample size and limited drug exposure, and further study is needed.

P105 Biologic/JAK preference in different IBD patient types

BACKGROUND: The IBD market is rapidly evolving as new biologic and small molecule agents are being approved such as ustekinumab in Crohn's disease and tofacitinib in ulcerative colitis (UC). This study sought to understand gastroenterologists' product preferences for certain patient types and to understand any shifts in preference with new agents to consider. METHODS: Each quarter, an independent healthcare agency surveys approximately 100 US gastroenterologists about the evolving treatment of IBD. To qualify, gastroenterologists must spend the majority of time in clinical practice, must be managing a minimum of 50 patients with IBD, and must be in practice between 2 and 35 years. Regional and practice setting quotas are applied in order to obtain a representative sample. The survey is administered online and respondents are compensated for their participation. The data are collected and analyzed in SPSS. RESULTS: Gastroenterologists describe over half of their UC patients as being “young, with active lifestyles”. This patient type has historically been strongly associated with adalimumab over other biologic agents, with 64% (n = 100) of respondents surveyed in April 2018 indicating that they would be most likely to use adalimumab for this patient category. However, with the availability of tofacitinib, which was approved in June 2018, preference for this large patient segment is changing. In the July 2018 wave of the survey, nearly one-quarter (23%) of gastroenterologists selected the new, oral JAK inhibitor as their most likely agent of choice for young, active patients, with adalimumab preference dipping to 54%. Tofacitinib was also selected by 16% of the gastroenterologists as being the drug of choice in patients with secondary TNF failures (waning efficacy), though the majority still prefer vedolizumab in this scenario (58%). When directly comparing adalimumab with tofacitinib in UC, gastroenterologists view adalimumab outperforming tofacitinib on all attributes associated with length of time in the market, but tofacitinib is already matching, or outpacing, adalimumab on many key attributes for treatment success including efficacy, adherence, tolerability, and sustained response. Analysis of the most recent prescription patterns, as assessed by physician allocation of their last 5 biologic/JAK prescriptions between April 2018 and July 2018 shows declining use of adalimumab (34% to 30%) with an increase of tofacitinib (0% to 5%). CONCLUSION(S): Adalimumab has long been the preferred biologic agent for the treatment of UC in younger, active patients, relatively unchallenged by any of the other biologics for this large patient sub-type. Early use of tofacitinib suggests that the advent of an oral advanced therapy option may soon rival adalimumab for preference in younger, active patients.

P011 A number needed to harm analysis of safety outcomes from randomized controlled trials of biologics and tofacitinib in ulcerative colitis

BACKGROUND: Emerging evidence on vedolizumab supports its safety profile given its unique gut-specific mechanism of action. Long-term safety is an important outcome when choosing between treatment options for moderately to severely active ulcerative colitis (UC). A systematic literature review and indirect treatment comparison examined published evidence on safety outcomes reported from randomized controlled trials (RCTs) of approved biologics and tofacitinib in UC. METHODS: MEDLINE, Embase, and Cochrane Library databases were searched from 1997 to July 2018 to identify RCTs reporting safety outcomes with biologic agents (vedolizumab, adalimumab, infliximab, golimumab, ustekinumab, certolizumab, natalizumab) and tofacitinib approved to treat moderately to severely active UC. All maintenance treatment studies (follow-up, 44–60 weeks) were included. A network meta-analysis estimated odds ratios (ORs) using vedolizumab as reference treatment for the following safety measures assessed at approximately 52 weeks: overall adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, overall infections, serious infections, and arthralgia. Number needed to harm (NNH), defined as the additional number of patients that would have to be treated with vedolizumab for one person to experience a safety outcome, was also calculated. A positive NNH denotes better safety with vedolizumab compared with other agents, with higher NNH values representing a correspondingly better safety profile for vedolizumab vs the given comparator treatment option. RESULTS: Of 3,102 publications identified, 6 RCTs (2 golimumab; 1 each vedolizumab, adalimumab, infliximab, and tofacitinib) were eligible for inclusion. Compared with vedolizumab, all ORs for SAEs trended higher for other treatment options (adalimumab: 1.99 [95% credible interval (CI) 0.84–4.70]; infliximab: 1.73 [0.76–3.97]; and tofacitinib: 1.66 [0.62–4.39]) or achieved statistical significance (golimumab: 2.55 [1.10–5.70]). The NNH values for SAEs were adalimumab: 18; infliximab: 24; golimumab: 12; and tofacitinib: 27. For AEs leading to discontinuation, ORs trended higher for other treatment options relative to vedolizumab (adalimumab: 2.32 [0.48–12.68]; infliximab: 3.48 [0.68–21.70]; golimumab: 3.43 [0.74–20.90]; tofacitinib: 1.61 [0.34–8.95]). The NNH values for AEs leading to discontinuation were adalimumab: 29; infliximab: 16; golimumab: 16; and tofacitinib: 63. For serious infections, ORs again trended higher for other treatment options (adalimumab: 1.23 [0.16–8.76]; infliximab: 1.78 [0.29–10.67]; golimumab: 4.09 [0.66–25.99]; tofacitinib: 1.28 [0.12–16.05]). The NNH values for serious infections were adalimumab: 333; infliximab: 100; golimumab: 25; and tofacitinib: 250. Similar numerical trends were observed with vedolizumab for the safety outcomes of overall AEs, overall infections, and arthralgia. CONCLUSION(S): In a network meta-analysis of RCTs, vedolizumab consistently demonstrated better safety profile trends relative to other approved treatment options for moderately to severely active UC. Vedolizumab had the highest NNH values for all safety outcomes, especially serious infections. These indirect comparison results were limited to RCT patient populations, and real-world studies in larger patient populations are needed to confirm these findings.

P035 Clostridium difficile infection in ulcerative colitis: Data from the tofacitinib clinical program and an insurance claims database

BACKGROUND: Patients with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), have a higher risk of Clostridium difficile infection (CDI) than the general population (1). The incidence of CDI is increasing among patients with IBD, and certain UC treatments may be associated with greater risk (1). We report CDI events in the tofacitinib UC clinical program, and the incidence of CDI among patients receiving other treatments for UC. METHODS: For the tofacitinib UC program, rates of CDI (patients with an adverse event [AE] of CDI, Clostridium difficile colitis, or Clostridium test-positive, plus concomitant oral metronidazole or vancomycin, counted once per cohort) are reported for Induction Cohort (patients from an 8-week Phase [P]2 and two 8-week P3 induction studies; placebo or tofacitinib 10 mg twice daily [BID; NCT00787202; NCT01465763; NCT01458951]); Maintenance Cohort (patients from a 52-week maintenance study; placebo or tofacitinib 5 or 10 mg BID [NCT01458574]); and Overall Cohort (all tofacitinib-treated patients in P2/3 induction and maintenance studies and an ongoing, open-label, long-term extension study [as of December 2016; NCT01470612]). Positive Clostridium difficile test at screening was an exclusion criterion for program entry. Overall Cohort incidence rate (IR) was calculated as number of unique patients with events per 100 patient-years (PY). For contextualization, CDI rates among patients receiving other UC medications were obtained from a retrospective cohort study utilizing data from the Truven MarketScan® Database, an administrative healthcare claims database in the US. Patients with moderately to severely active UC, with either an inpatient or outpatient diagnosis code of CDI, plus a prescription for oral therapy (including metronidazole, vancomycin, and fidaxomicin) within 14 days of CDI diagnosis (observation period: October 1, 2010–September 30, 2015), were included. Truven cohort IRs were calculated as number of patients with events per 100 PY. RESULTS: In the tofacitinib Induction Cohort, CDI occurred in 3 patients (placebo, 1/282 [0.4%]; tofacitinib 10 mg BID, 2/938 [0.2%]). In the Maintenance Cohort, CDI occurred in 3 patients (placebo, 3/198 [1.5%]; tofacitinib 5 or 10 mg BID, 0/394 [0.0%]). In the Overall Cohort of all tofacitinib-treated patients (1,664 PY of follow-up), CDI occurred in 8/1,157 patients (0.7%), with an IR (95% confidence interval [CI]) of 0.48 (0.21, 0.95). Two cases were reported as serious AEs. All were mild (n = 4) or moderate (n = 4) in severity; 6 continued with study treatment, one temporarily discontinued, one permanently discontinued. All CDI cases resolved with treatment. In the Truven Cohort, 160 CDI events occurred during 4,918 PY of follow-up, with an overall CDI IR (95% CI) of 3.25 (2.77, 3.80); of which 116 were CDI-associated hospitalizations (4,936 PY of follow-up). Among patients receiving azathioprine, 6-mercaptopurine, or tumor necrosis factor inhibitors, CDI IRs were 3.23 (2.18, 4.62), 2.31 (1.26, 3.87), and 3.58 (2.95, 4.29), respectively. CONCLUSION(S): In the tofacitinib UC program, CDI rates among patients receiving tofacitinib were similar to or lower than those observed with placebo. The IR among patients receiving tofacitinib was numerically lower than those observed for immunomodulators and tumor necrosis factor inhibitors in the Truven Cohort.

P034 Assessment of age as a risk factor for adverse events in patients from the tofacitinib ulcerative colitis clinical program

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.

P036 Impact of prior immunosuppressant and tumor necrosis factor inhibitor therapies on tofacitinib efficacy and safety in patients with ulcerative colitis

BACKGROUND: Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The tofacitinib UC program comprises Phase (P)2 and P3 induction studies, a P3 maintenance study, and an ongoing open-label extension study (1). We report efficacy and safety of tofacitinib in the UC program in patients with/without prior tumor necrosis factor inhibitor (TNFi) failure and/or immunosuppressant failure. METHODS: Efficacy data are reported from OCTAVE Induction 1 and 2 (NCT01465763 and NCT01458951; pooled data), and OCTAVE Sustain (NCT01458574). We evaluated rates of remission stratified by prior TNFi failure (yes/no) and prior immunosuppressant failure (yes/no). Where there were sufficient adverse events (AEs) to analyze, effects of prior TNFi failure, and prior immunosuppressant exposure on AEs of special interest (herpes zoster [HZ], serious infections, and adjudicated non-melanoma skin cancer [NMSC]), were evaluated using Cox regression analysis in tofacitinib-treated patients in the UC program (December 2016 data cut; N = 1,157; 1,613 patient-years' exposure). RESULTS: Among 1,139 patients (placebo: n = 234; tofacitinib 10 mg BID: n = 905) treated in OCTAVE Induction 1 and 2, 51.7% had prior TNFi failure and 71.9% had prior immunosuppressant failure. For patients with TNFi failure, Week (Wk) 8 remission rates were: placebo: 0.8%; 10 mg BID: 11.4% (difference from placebo [Δ] = 10.6%); rates for patients without TNFi failure were 11.8% and 24.1%, respectively (Δ = 12.3%). In patients with immunosuppressant failure, Wk8 remission rates were: placebo 3.2%; 10 mg BID: 15.6% (Δ = 12.4%); rates in patients without immunosuppressant failure were 11.8% and 23.0%, respectively (Δ = 11.1%). Among 593 patients treated in OCTAVE Sustain (placebo: n = 198; 5 mg BID: n = 198; 10 mg BID: n = 197), 44.7% had prior TNFi failure and 69.6% prior immunosuppressant failure at induction baseline. For patients with TNFi failure, Wk52 remission rates were: placebo: 11.2%; 5 mg BID: 24.1% (Δ = 12.9%); 10 mg BID: 36.6% (Δ = 25.3%); rates for patients without TNFi failure were: placebo: 11.0%; 5 mg BID: 41.7% (Δ = 30.7%); 10 mg BID: 44.2% (Δ = 33.2%). For patients with immunosuppressant failure, Wk52 remission rates were: placebo: 7.8%; 5 mg BID: 29.4% (Δ = 21.6%); 10 mg BID: 37.6% (Δ = 29.8%); rates for patients without immunosuppressant failure were: placebo 17.4%; 5 mg BID: 47.3% (Δ = 29.9%); 10 mg BID: 48.2% (Δ = 30.8%). Among all tofacitinib-treated patients in the UC program with prior TNFi failure, 505/583 (86.6%) had AEs and 92/583 (15.8%) had serious AEs. For patients without prior TNFi failure, 431/541 (79.7%) had AEs and 75/541 (13.9%) had serious AEs. Prior TNFi failure (hazard ratio [95% confidence interval]: 1.9 [1.2–3.2]) was identified as a significant risk factor for HZ, and for NMSC (11.3 [1.4–88.3]). Prior immunosuppressant exposure was not identified as a significant risk factor for AEs of special interest in Cox regression analyses. CONCLUSION(S): In patients with UC, prior TNFi/immunosuppressant failure did not preclude benefit from tofacitinib induction or maintenance therapy. Prior TNFi failure was associated with greater risk for HZ and NMSC. HZ cases in the UC program were typically non-complicated and manageable with standard antiviral therapy (2).

Evaluating tofacitinib citrate in the treatment of moderate-to-severe active ulcerative colitis: design, development and positioning of therapy.

The etiology of ulcerative colitis (UC) is complex and involves a host of genetic, epigenetic and environmental factors. Over the last thirty years, signaling pathways like the Janus kinase (JAK) signaling pathway have been implicated in its pathogenesis. Pharmacologic blockade of this pathway is available through several small molecule inhibitors, including tofacitinib. Tofacitinib is an orally administered pan-JAK inhibitor that was first approved by the Food and Drug Administration (FDA) for use in rheumatologic disorders such as rheumatoid arthritis and psoriatic arthritis. The FDA approved its use in moderate-to-severe active ulcerative colitis in 2018. The aim of this review will be to discuss the role of tofacitinib in ulcerative colitis. We will discuss the role of JAK-STAT signaling, clinical data available for tofacitinib, and the safety profile for this therapy. Tofacitinib’s place in the UC management algorithm is currently being debated. This effective oral therapy is poised to be a mainstay of UC therapeutics. This review will highlight the key clinical features and detail the UC experience to date.

796 – Real-World Effectiveness of Tofacitinib in Ulcerative Colitis; a Multi-Center Study

796 – Real-World Effectiveness of Tofacitinib in Ulcerative Colitis; a Multi-Center Study

P344 Real-world effectiveness of tofacitinib in ulcerative colitis: a multi-centre study

P344 Real-world effectiveness of tofacitinib in ulcerative colitis: a multi-centre study

Characterization of Creatine Kinase Levels in the Tofacitinib Ulcerative Colitis Development Program

Characterization of Creatine Kinase Levels in the Tofacitinib Ulcerative Colitis Development Program

Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis.

BackgroundActive inflammatory bowel disease increases the risk of adverse pregnancy outcomes. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). As a small molecule, tofacitinib is likely to cross the placental barrier; however, information on the effects of tofacitinib on pregnancy outcomes is limited. We report pregnancy and newborn outcomes among patients in UC clinical studies with prenatal (maternal/paternal) exposure to tofacitinib.MethodsPregnancies with maternal/paternal exposure to tofacitinib were identified and outcomes reported in 5 tofacitinib UC interventional studies (up to March 2017). Outcomes from tofacitinib rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis interventional studies, and RA noninterventional postapproval safety studies, spontaneous adverse event reporting, and registry data are also reported.ResultsOf 1157 patients enrolled in the UC interventional studies, 301 were women of childbearing age. Eleven cases of maternal exposure and 14 cases of paternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy were identified. Outcomes included 15 healthy newborns, no fetal deaths, no neonatal deaths, no congenital malformations, 2 spontaneous abortions, and 2 medical terminations. Outcomes across other tofacitinib studies and postmarketing cases were consistent, with a healthy newborn being the most common outcome and no fetal deaths.ConclusionsBased on the limited data available, pregnancy and newborn outcomes among patients with prenatal (maternal/paternal) exposure to tofacitinib in UC studies appear similar to those reported for other tofacitinib clinical study populations and the general population.

Sa1750 - The Effect of Tofacitinib on Serum Lipids and Cardiovascular Safety in Patients with Ulcerative Colitis - Results from the Tofacitinib Ulcerative Colitis Clinical Program

Sa1750 - The Effect of Tofacitinib on Serum Lipids and Cardiovascular Safety in Patients with Ulcerative Colitis - Results from the Tofacitinib Ulcerative Colitis Clinical Program

OP033 The effect of tofacitinib on serum lipids and cardiovascular safety in patients with ulcerative colitis: results from the tofacitinib ulcerative colitis clinical programme

OP033 The effect of tofacitinib on serum lipids and cardiovascular safety in patients with ulcerative colitis: results from the tofacitinib ulcerative colitis clinical programme

Pregnancy Outcomes in the Tofacitinib Ulcerative Colitis OCTAVE Studies

Introduction: Compared with controls, pregnant women with ulcerative colitis (UC) are at a higher risk of adverse outcomes incl. spontaneous abortion, preterm birth and low birth weight.1,2 Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for UC. Tofacitinib is feticidal and teratogenic in rats and rabbits at exposures 146 and 13 times, respectively, the human dose of 5 mg twice daily (BID). There are no adequate and well-controlled studies of tofacitinib in pregnant women. Methods: We report pregnancy outcomes from 3 randomized, placebo (PBO)-controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951; OCTAVE Sustain, NCT01458574) and 1 ongoing open-label extension study (OCTAVE long-term study, NCT01470612) of tofacitinib monotherapy in patients (pts) with moderate to severe UC.3 Pregnancy outcomes following maternal or paternal exposure to tofacitinib 5 or 10 mg BID were identified from Pfizer's internal safety database up to March 23, 2017. Trial protocols required use of highly effective contraception for women of childbearing potential, and for the study drug to be discontinued in any female pts that became pregnant. Results: 1139 unique pts (incl. PBO) enrolled in the OCTAVE trials; 296 were women of childbearing age. There were 25 pregnancies reported with exposure to tofacitinib. Of these, 11 were cases of maternal exposure, all during the 1st trimester, including: 2 (18.2%) spontaneous abortions (5 mg BID, n=1; 10 mg BID, n=1), 2 (18.2%) medical terminations (both 10 mg BID), 4 (36.4%) healthy newborns (all 10 mg BID) and 3 (27.3%) lost to follow up (all 10 mg BID). Of the 14 cases of paternal exposure, 11 (78.6%) were healthy newborns (5 mg BID, n=2; 10 mg BID, n=9) and 3 (21.4%) were pending/lost to follow up (5 mg BID, n=1; 10 mg BID, n=2). There were no cases of fetal death or congenital malformation. Conclusion: Based on limited data and follow up available, pregnancy and newborn outcomes among pts with UC with prenatal (maternal/paternal) exposure to tofacitinib appear to be similar to those reported for the UC population and those previously reported in pts with rheumatoid arthritis and psoriasis.4 Larger long-term follow-up studies are needed to examine safety of tofacitinib during pregnancy. Funded by Pfizer Inc.Table: Table. Summary of pregnancy outcomes in the OCTAVE program