Open-label Long-term Extension Study Research Articles

Mitapivat Treatment Reduces Levels of Interference in Work/School Activity for Adult Patients with Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia. It is associated with a range of acute and long-term complications and negatively impacts health-related quality of life. Patients (pts) with PK deficiency report daily social and physical limitations, which negatively impact various aspects of their lives, including the ability to perform at their full potential at work or school. Mitapivat is a first-in-class, oral, allosteric activator of PK, approved by the United States Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, and by the European Union European Medicines Agency and the Medicines and Healthcare products Regulatory Agency in Great Britain for the treatment of PK deficiency in adults. Mitapivat has shown sustained and clinically meaningful improvements in the disease impact of PK deficiency measured by two disease-specific patient-reported outcome (PRO) instruments, the PK Deficiency Impact Assessment (PKDIA) and the PK Deficiency Diary (PKDD), in the pivotal ACTIVATE trial (NCT03548220) and its long-term extension (LTE) study (NCT03853798) in adult pts with PK deficiency who were not receiving regular transfusions. In this post hoc analysis, new PRO data are reported from ACTIVATE and its LTE study focusing on the impact of PK deficiency on work or school performance and how treatment with mitapivat impacts this over time in these pts. Methods: In the global, phase 3, placebo (PBO)-controlled ACTIVATE trial, adult pts with PK deficiency who were not receiving regular transfusions were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 weeks (wks). Pts who completed ACTIVATE were eligible to continue in the open-label LTE study, where all pts received mitapivat (5/20/50 mg twice daily or dose at last visit of ACTIVATE). Pts from ACTIVATE who participated in the LTE study were categorized into either the mitapivat-to-mitapivat arm (M/M) or the PBO-to-mitapivat arm (P/M). In the PKDIA questionnaire, pts who worked or went to school over the 7 days prior to a scheduled visit were asked to rate how often their PK deficiency interfered with their ability to perform to their full potential at work or school, using an 11-point numeric rating scale (work/school interference score; ranging from 0 [none of the time] to 10 [all of the time]). Changes in the work or school interference score from baseline (BL; defined as the last complete assessment before start of study treatment in ACTIVATE) were summarized descriptively by treatment arm over the fixed-dose period of ACTIVATE (24 wks) and up to Wk 60 of the LTE study (84 wks overall). Results: Among the 80 randomized adult pts with PK deficiency who were not receiving regular transfusions in ACTIVATE, 54 (67.5%) attended work/school at BL (28 pts randomized to mitapivat, 26 pts to PBO), 3 pts found it too difficult to attend, 21 did not attend for reasons unrelated to PK deficiency, and data were unavailable for 2. The mean (SD) work/school interference score for the 54 pts at BL was 4.0 (2.49) and was similar for the mitapivat (4.2 [2.42]) and PBO (3.9 [2.61]) arms. At Wk 24, 37 pts worked or went to school (including 22 in the mitapivat arm and 15 in the PBO arm), 5 pts found it too difficult to attend, 32 pts did not attend for reasons unrelated to PK deficiency, and data were unavailable for 6 pts. Change from BL in work/school interference score was compared for the 33 pts who attended work/school at both BL and Wk 24. Pts treated with mitapivat (n=19) had a reduction in the work/school interference score (mean [SD] change: -1.5 [1.74]) while negligible change (0.1 [2.41]) was observed among PBO pts (n=14). Notably, this reduction in score was sustained among M/M pts up to Wk 60 of the LTE. Furthermore, P/M pts experienced a reduction in the work or school interference score after starting mitapivat treatment in the LTE period, which was consistent with the improvements seen in the M/M arm during the ACTIVATE trial (Figure). Conclusions: In this post hoc analysis, interference in work or school performance was observed in adult pts with PK deficiency who were not receiving regular transfusions. Treatment with mitapivat showed sustained improvements in work or school performance over time. These data continue to support the potential for mitapivat to provide long-term benefits and reduced interference in work or school performance in these pts.

Tafamidis Efficacy Among Octogenarian Patients in the Phase 3 ATTR-ACT and Ongoing Long-Term Extension Study

BackgroundTafamidis was approved to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of findings from the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). ObjectivesThis study was a post hoc analysis exploring tafamidis efficacy in octogenarian patients. MethodsAnalysis of patients aged <80 and ≥80 years in ATTR-ACT and its ongoing open-label long-term extension (LTE) study, where all patients receive tafamidis. ResultsAfter 30 months in ATTR-ACT, least squares (LS) mean change from baseline in 6-minute walk test (6MWT) distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score were smaller (all P < 0.05) in patients aged ≥80 years treated with tafamidis (n = 51) vs placebo (n = 37). At the LTE study interim analysis, patients aged ≥80 years treated continuously with tafamidis had a smaller decline in KCCQ-OS score (P < 0.05) and trended toward longer median survival (45 vs 27 months; all-cause mortality HR: 0.6828 [95% CI: 0.4048-1.1517]; P = 0.1526) than those initially treated with placebo in ATTR-ACT. Similar efficacy was observed in patients aged <80 years in ATTR-ACT, including smaller LS mean change from baseline in 6MWT distance, NT-proBNP concentration, and KCCQ-OS score, and lower rate of cardiovascular-related hospitalizations with tafamidis (n = 125) vs placebo (n = 140). In the LTE study, patients aged <80 years treated continuously with tafamidis had a longer median survival (80 vs 41 months; HR = 0.4513 [95% CI: 0.3176-0.6413]; P < 0.0001) and a smaller decline in KCCQ-OS score than those initially treated with placebo. ConclusionsThe findings demonstrate tafamidis efficacy for patients with ATTR-CM both in those aged <80 and those aged ≥80 years. (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]; NCT01994889/Long-term Safety of Tafamidis in Subjects With Transthyretin Cardiomyopathy; NCT02791230)

Modeling of Treatment Outcomes with Tofacitinib Maintenance Therapy in Patients with Ulcerative Colitis: A Post Hoc Analysis of Data from the OCTAVE Clinical Program.

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). This post hoc analysis assessed whether various statistical techniques could predict outcomes of tofacitinib maintenance therapy in patients with UC. Data from patients who participated in a 52-week, phaseIII maintenance study (OCTAVE Sustain) and an open-label long-term extension study (OCTAVE Open) were included in this analysis. Patients received tofacitinib 5 or 10mg twice daily (BID) or placebo (OCTAVE Sustain only). Logistic regression analyses were performed to generate models using clinical and laboratory variables to predict loss of responder status at week8 of OCTAVE Sustain, steroid-free remission (defined as a partial Mayo score of 0-1 in the absence of corticosteroid use) at week52 of OCTAVE Sustain, and delayed response at week8 of OCTAVE Open. Furthermore, differences in loss of response/discontinuation patterns between treatment groups in OCTAVE Sustain were established. The generated prediction models demonstrated insufficient accuracy for determining loss of response at week8, steroid-free remission at week52 in OCTAVE Sustain, or delayed response in OCTAVE Open. Both tofacitinib doses demonstrated comparable response/remission patterns based on visualizations of disease activity over time. The rectal bleeding subscore was the primary determinant of disease worsening (indicated by an increased total Mayo score), and the endoscopy subscore was the primary determinant of disease improvement (indicated by a decreased total Mayo score). Visualizations of disease activity subscores revealed distinct patterns among patients with UC that had disease worsening and disease improvement. The statistical models assessed in this analysis could not accurately predict loss of responder status, steroid-free remission, or delayed response to tofacitinib. Possible reasons include the small sample size or missing data related to yet unknown key variables that were not collected during these trials.

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program.

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild-moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild-moderate in severity, and most resolved with treatment.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

P286 Sustained improvement in health-related quality of life outcomes in patients with Ulcerative Colitis with long-term tofacitinib treatment in the open-label extension study, OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib induction and maintenance therapy has previously been shown to improve health-related quality of life (HRQoL) outcomes. Here, we present HRQoL data from patients (pts) with UC who received tofacitinib 5 or 10 mg twice daily (BID) in the Phase 3 open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), up to Month (M)72. Methods Proportions of pts with an Inflammatory Bowel Disease Questionnaire (IBDQ) total score ≥170, and EuroQol-5D (EQ-5D) and Short Form-36 Health Survey (SF-36) scores were analysed up to M72 in 4 subpopulations in the OLE study: ‘maintenance remitters’ completed OCTAVE Sustain in remission and received tofacitinib 5 mg BID in the OLE study; in contrast, ‘maintenance treatment failures’ (induction responders who experienced treatment failure), ‘maintenance non-remitters’ and ‘induction non-responders (IndNR)’ received tofacitinib 10 mg BID in the OLE study (Figure 1). Data were analysed for each subpopulation overall and stratified by prior tumour necrosis factor inhibitor (TNFi) failure, prior immunosuppressant failure and baseline corticosteroid use. Results Baseline demographics and clinical characteristics for each subpopulation are shown in Table 1. Among the 163 maintenance remitters, HRQoL outcomes were maintained up to M72: 80.0% of pts had an IBDQ total score ≥170 (Figure 1); changes from baseline in EQ-5D scores up to M72 and SF-36 scores up to M33 were minimal (eg M72 EQ-5D utility score -0.07 [standard deviation 0.10]; M33 SF-36 physical functioning score -1.3 [8.3]). Among pts continuing long-term tofacitinib treatment, improvement in IBDQ total score was maintained/achieved by M2 (first post-baseline assessment), and was stable up to M72, with maintenance treatment failures and IndNR subpopulations experiencing the largest improvements from baseline (Figure 1). Similar trends were observed for improvement in EQ-5D and SF-36 scores. Improvements in HRQoL outcomes were independent of prior TNFi failure, prior immunosuppressant failure or baseline corticosteroid use, eg in maintenance remitters with prior TNFi failure, 90.9% of pts had IBDQ total score ≥170 at M60 vs 88.9% of pts without prior TNFi failure. Conclusion Sustained beneficial effects in HRQoL were observed among pts continuing long-term tofacitinib treatment in OCTAVE Open. In maintenance remitters, improvements in all HRQoL outcomes were maintained with tofacitinib therapy. In pts who entered the OLE study not in remission and received tofacitinib 10 mg BID, HRQoL improvements were observed within the first 2 months, and were maintained up to M72, regardless of treatment history including prior TNFi failure.

OP38 Tofacitinib for the treatment of Ulcerative Colitis: An integrated summary of safety data from the global OCTAVE and RIVETING clinical trials

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). We report updated tofacitinib safety analyses from the tofacitinib UC clinical programme, with inclusion of a 6-month interim analysis of data from the P3b/4 study, up to 7.8 years of tofacitinib exposure. Methods This analysis included 1157 patients (pts) receiving tofacitinib 5 or 10 mg BID from completed P2/P3/OLE studies, and the ongoing P3b/4 study (as of 20 Feb 2020; Overall+P3b/4 Cohort). Proportions and incidence rates (IRs; unique pts with events/100 pt-years [PY] of exposure) were evaluated for deaths and adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE) and gastrointestinal perforations were adjudicated. Results Table 1 shows demographics and clinical characteristics. In the Overall+P3b/4 Cohort, 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID; 955 (83%) received a predominant dose of 10 mg BID; 397/1157 (34.3%) pts had received tofacitinib for &amp;gt;4.1 years. Median treatment duration was 623 (range, 1–2850) days (2999.7 PY of exposure). Table 2 shows safety data for AEs of special interest in the Overall+P3b/4 Cohort. IRs (95% confidence intervals) for all tofacitinib doses: deaths, 0.23 (0.09, 0.46); serious infections, 1.69 (1.26, 2.21); herpes zoster (non-serious and serious), 3.30 (2.67, 4.04); OIs, 1.03 (0.70, 1.46); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 (0.55, 1.24); NMSC, 0.73 (0.45, 1.10); MACE, 0.29 (0.13, 0.55); deep vein thrombosis, 0.03 (0.00, 0.18); pulmonary embolism, 0.19 (0.07, 0.42); and gastrointestinal perforations, 0.10 (0.02, 0.28). IRs for AEs of special interest were similar to prior Overall Cohort analyses.1 Conclusion The safety profile of tofacitinib in pts with UC from the tofacitinib UC clinical programme was generally consistent with that of other UC therapies, including biologics, with the exception of herpes zoster.2 IRs for AEs of special interest have remained stable over an extended period of time (up to 7.8 years) with inclusion of final data from the OLE study and an interim analysis of data from the P3b/4 study.1,3

P477 Rectal bleeding and stool frequency improvement with tofacitinib retreatment in patients with Ulcerative Colitis after treatment interruption: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Patients may require retreatment following treatment interruption for reasons such as adverse events or pregnancy.1 In the tofacitinib UC clinical programme, patients who responded to tofacitinib 10 mg BID during induction, and experienced treatment failure whilst receiving placebo during maintenance (OCTAVE Sustain) and subsequently received tofacitinib 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the retreatment subpopulation. The efficacy and safety of tofacitinib in the retreatment subpopulation have previously been reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the retreatment subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall retreatment subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline), and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 101 patients were included in the retreatment subpopulation, of which 46 (45.5%) had prior TNFi failure. Overall, at M1 and M6 of OCTAVE Open, 83.2% and 76.2% of patients had rectal bleeding improvement, respectively (Figure 1). Corresponding values for stool frequency improvement were 70.3% and 75.2%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Mean decrease from baseline in PMS, RBS and SFS at M1 was similar in patients with and without a clinical response at M2 (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after 8–52 weeks of treatment interruption, retreatment with tofacitinib 10 mg BID resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Reference 1. Panés J et al. J Crohns Colitis 2021. Epub ahead of print.

P378 Rectal bleeding and stool frequency improvement with tofacitinib dose escalation to, 10 mg BID in patients with Ulcerative Colitis following loss of response on tofacitinib, 5 mg BID maintenance therapy: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical programme, patients who responded to tofacitinib, 10 mg BID during induction, and experienced treatment failure whilst receiving tofacitinib, 5 mg BID during maintenance (OCTAVE Sustain) and subsequently received tofacitinib, 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the dose escalation subpopulation. The efficacy and safety of tofacitinib in the dose escalation subpopulation have been previously reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the dose escalation subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall dose escalation subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline) and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 57 patients were included in the dose escalation subpopulation, of which, 28 (49.1%) had prior TNFi failure. Overall, at M1 and M6, of OCTAVE Open, 59.6% and, 66.7% of patients had rectal bleeding improvement, respectively (Figure, 1). Corresponding values for stool frequency improvement were, 50.9% and, 64.9%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Patients with a clinical response at M2 had a numerically greater mean decrease from baseline in PMS, RBS and SFS at M1 than those without (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after, 8–52 weeks of treatment with tofacitinib, 5 mg BID (following reduction from induction tofacitinib, 10 mg BID), dose escalation back to, 10 mg BID generally resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Furthermore, early improvement in RBS and/or SFS at M1 may indicate likelihood of recapturing response at M2 with dose escalation from tofacitinib, 5 to, 10 mg BID. Reference 1. Sands BE et al. Aliment Pharmacol Ther, 2020;, 51:, 271–280.

S777 Tofacitinib for the Treatment of Ulcerative Colitis: Up to 7.8 Years of Safety Data from Global Clinical Trials

S777 Tofacitinib for the Treatment of Ulcerative Colitis: Up to 7.8 Years of Safety Data from Global Clinical Trials

P334 Tofacitinib for the treatment of Ulcerative Colitis: Analysis of malignancy rates from the Ulcerative Colitis clinical programme

Abstract Background 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 tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020). Methods Malignancies were evaluated from 3 randomised, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612). Three cohorts were analysed: Induction (P3 induction studies), Maintenance (P3 maintenance study) and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies; data from the previous data cut [May 2019] are also reported for comparison). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose &amp;lt;15 mg or ≥15 mg, respectively (82.1% of patients received PD 10 mg BID). An independent adjudication committee reviewed potential malignancies. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) were evaluated for malignancies (excluding non-melanoma skin cancer [NMSC]) and NMSC. Results 1124 patients were evaluated for malignancies (2809.4 patient-years of tofacitinib exposure; up to 7.8 years of treatment; median duration of 685.5 days). No malignancies (excluding NMSC) occurred in Induction Cohort patients. Malignancies (excluding NMSC) occurred in 1 Maintenance Cohort patient (who was receiving placebo) and in 25 Overall Cohort patients (IR 0.86 [95% confidence interval (CI) 0.56, 1.27]: PD tofacitinib 5 mg BID n=5, IR 0.63 [95% CI 0.20, 1.47]; PD tofacitinib 10 mg BID n=20, IR 0.95 [95% CI 0.58, 1.46]); 5 new cases since May 2019 (Table).1 NMSC events in the Induction and Maintenance Cohorts were previously reported (Table).1 NMSC events occurred in 21 Overall Cohort patients (IR 0.73 [95% CI 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (95% CI 0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (95% CI 0.44, 1.25); 2 new cases since May 2019 (Table).1 Conclusion There was no apparent clustering of types of malignancy, excluding NMSC. Malignancies (excluding NMSC) and NMSC IRs remained stable over time, being comparable to those previously reported in the tofacitinib UC clinical programme.1 In this analysis, malignancies (excluding NMSC) and NMSC IRs were similar to those in patients with UC treated with tumour necrosis factor inhibitors, as reported from claims data (IRs of 0.63 and 1.69, respectively).2 References

P260 An analysis of non-melanoma skin cancer rates in the tofacitinib Ulcerative Colitis clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020). Methods NMSC events were evaluated from 3 randomised, placebo (PBO)-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612), as 3 cohorts: Induction (P3 induction studies [patients (pts) receiving tofacitinib 10 mg twice daily (BID) or PBO]); Maintenance (P3 maintenance study [pts receiving tofacitinib 5 or 10 mg BID or PBO]); Overall (pts receiving tofacitinib 5 or 10 mg BID in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose &amp;lt;15 or ≥15 mg, respectively (82% of pts received PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis. Results 1124 pts were evaluated for NMSC (2809.4 pt-years of tofacitinib exposure; up to 7.8 years of treatment; median duration 685.5 days). NMSC events in Induction and Maintenance were previously reported (Table 1).1 In Overall, NMSC occurred in 21 pts (IR 0.73 [95% confidence interval (CI) 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (0.44, 1.25) (Table 1); 2 new cases since May 2019.1 Eleven pts had squamous cell carcinoma and 15 pts had basal cell carcinoma; 5 pts had both. No NMSC was metastatic or led to discontinuation. IRs by time interval and subgroup are reported (Table 2). Prior NMSC (hazard ratio [HR] 12.08 [95% CI 4.20, 34.76]) and age (per 10-year increase, HR 2.01 [1.38, 2.93]) were significant risk factors for NMSC in the multivariable analysis. Prior immunosuppressant use was not a significant risk factor in either the multivariable or univariate analyses. Conclusion In this analysis, NMSC IRs for tofacitinib were similar to those in pts with UC treated with biologics2 and those previously reported in the tofacitinib UC clinical programme.1 NMSC events were more likely to occur in pts with recognised NMSC risk factors: prior NMSC and increasing age.3 Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs remained stable over time, up to 7.8 years of exposure. References

DOP61 Impact of prior tumour necrosis factor inhibitor failure and prior corticosteroid use on the maintenance of efficacy of tofacitinib following dose reduction in patients with Ulcerative Colitis who were in stable remission: 6-month data from the double-blind, randomised RIVETING study

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). RIVETING (NCT03281304) is an ongoing, double-blind, randomised, parallel-group study designed to evaluate the efficacy and safety of dose reduction to tofacitinib 5 mg twice daily (BID) vs remaining on 10 mg BID in patients (pts) with UC in stable remission on tofacitinib 10 mg BID maintenance therapy. Eligible pts had received tofacitinib 10 mg BID for ≥2 consecutive years in an open-label, long-term extension (OLE) study (NCT01470612), and had been in stable remission for ≥6 months (M) and corticosteroid (CS)-free for ≥4 weeks prior to enrolment.1 We aimed to evaluate tofacitinib efficacy outcomes by the number of prior tumour necrosis factor inhibitors (TNFi) failed and by prior CS use. Methods We evaluated the efficacy of tofacitinib 5 mg BID at Month 6 of RIVETING, based on the number of prior TNFi failed (0, 1 or &amp;gt;1), CS use (yes/no) and CS dose (&amp;lt;15 mg/day and ≥15 mg/day) at baseline (BL) of OCTAVE Induction 1&amp;2 and at OLE study BL. CS were prohibited in RIVETING. Results Of the 70 pts randomised to dose-reduce to tofacitinib 5 mg BID, 43 pts had no prior TNFi failure, 17 pts had previous failure with 1 TNFi and 10 pts had previous failure with &amp;gt;1 TNFi. At Month 6, modified Mayo (mMayo) score remission was maintained in 79.1%, 70.6% and 80.0% of pts who had previous failure with 0, 1 and &amp;gt;1 TNFi, respectively. At Month 6, the change from RIVETING BL total Mayo score, mMayo score, partial Mayo score (PMS) and modified PMS was similar across TNFi subgroups (Table 1). Of pts who enrolled into RIVETING, 26 pts were receiving CS (9 received &amp;lt;15 mg/day and 17 received ≥15 mg/day) at induction study BL, and 7 pts were receiving CS at OLE study BL. At Month 6, rates of mMayo score remission were numerically higher in pts with CS use at induction study BL (84.6%) vs those without CS use (72.7%). The rate of mMayo score remission was numerically higher in pts without CS use (77.8%) vs pts with CS use at OLE BL (71.4%), although pt numbers were very low in the CS-use group. These trends were also observed for other efficacy endpoints (Table 2). The Month 6 change from RIVETING BL mMayo score and total Mayo score was numerically higher in pts with vs pts without CS use at induction BL (0.7 and 1.1 vs 0.6 and 0.9, respectively) and OLE BL (1.0 and 1.3 vs 0.6 and 0.9, respectively) (Table 2). Conclusion In pts who were in stable remission for &amp;gt;6M, efficacy endpoints were maintained following dose reduction to tofacitinib 5 mg BID, regardless of the number of prior TNFi failures or prior CS use. These analyses are post hoc and limited by the small sample size. Reference

Infigratinib in Children With Achondroplasia (ACH): Design of PROPEL2 - A Phase 2, Open-Label, Dose-Escalation and Dose-Expansion Study

Abstract Background: ACH, the most common non-lethal form of skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Current treatment options are non-targeted, ineffective, or painful interventions aimed at preventing or treating complications. Infigratinib is an orally bioavailable and selective FGFR1-3 tyrosine kinase inhibitor in development for FGFR-related conditions. In vitro data with infigratinib showed inhibition of FGFR1-3 activity with reversal of established growth arrest in chondrocytes. In vivo studies revealed dose-dependent improvements in foramen magnum and long bone length in Fgfr3Y367C/+ mice following treatment with infigratinib. Methods: PROPEL2 is a prospective, phase 2, open-label study of infigratinib in children with ACH. Children 3-11 years of age with ACH who have completed at least 6 months of observation in the observational PROPEL study are eligible to participate. PROPEL2 consists of dose escalation with an extended treatment phase, designed as dose finding, followed by a dose-expansion phase to confirm the selected dose and to provide evidence of efficacy. The primary endpoints of the dose-escalation/extended treatment phase are treatment-emergent adverse events and change from baseline in annualized growth velocity. Subjects (n=40) will be enrolled in ascending dose cohorts of approximately 10 subjects/cohort (4 cohorts planned) and treated for 6 months at their assigned dose, continuing for an additional 12 months with dose modifications as required. Up to 20 new subjects will be enrolled in the dose-expansion phase and receive infigratinib (mini-tablets, administered orally once daily) for 12 months. Secondary objectives include: safety/tolerability of infigratinib; changes from baseline in anthropometric parameters, including body proportions; and the pharmacokinetic/pharmacodynamic profile of infigratinib. An exploratory objective is evaluation of changes in ACH disease burden. Current Status: PROPEL2 is currently enrolling - the first subject was entered in July 2020. The planned total enrollment is 60 children with ACH (n=40 in the dose-escalation/extended treatment phase; n=20 in the dose-expansion phase). Following completion of PROPEL2, subjects have the opportunity to enroll in an open-label long-term extension study to assess the safety and efficacy of long-term administration of infigratinib in children with ACH.

A pooled safety analysis of peficitinib (ASP015K) in Asian patients with rheumatoid arthritis treated over a median of 2 years

Objective To evaluate the safety of peficitinib for the treatment of rheumatoid arthritis (RA) in Asian patients. Methods Safety data from one Phase 2b, two Phase 3, and one open-label long-term extension study [data cut-off 31 May 2018] were pooled into Phase 3 studies (peficitinib 100 and 150 mg/day, and placebo) and Phase 2/3 studies (all peficitinib-treated patients). Incidence rates per 100 patient-years (PY) of adverse events (AEs) of special interest were calculated. Results Overall, 1052 patients received peficitinib for 2336.3 PY of exposure (median 2.1 years); four deaths occurred, including one death after the studies. AE incidence was similar across peficitinib 100 and 150 mg/day groups (Phase 3 studies). Respective peficitinib and placebo incidence rates (95% confidence interval) per 100 PY were 2.9 (1.9, 4.6) and 0.0 for serious infections, 5.7 (4.2, 7.9) and 2.3 (0.6, 9.4) for herpes zoster-related disease, and 0.6 (0.2, 1.6) and 1.2 (0.2, 8.3) for malignancies (excluding non-melanoma skin cancer) (Phase 3 studies), and 0.1 (0.0, 0.3) for venous thromboembolism in all peficitinib-treated patients (Phase 2/3 studies). Conclusion Peficitinib was well tolerated in Asian patients with RA over a median of 2 years, with no observed dose or temporal dependency for AEs with prolonged administration.

Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials.

Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n=11, incidence rates (IR)=0.5], cellulitis (n=6, IR=0.3) and pneumonia (n=3, IR=0.1). There were four opportunistic infections (IR=0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR=9.6; 4-mg IR=14.5) were lower vs. the placebo-controlled data set (2-mg IR=12.4; 4-mg IR=21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.

S0665 Clostridium difficile Infection in Patients With Ulcerative Colitis Treated With Tofacitinib in the Ulcerative Colitis Program: An Update as of May 2019

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Patients (pts) with UC are susceptible to C. difficile infection (CDI) (1). In the tofacitinib UC clinical program, previous analyses showed CDI rates among tofacitinib-treated pts to be similar or numerically lower than placebo (PBO)-treated pts and pts treated with immunomodulators and TNFi in a generally comparable claims-based observational cohort (2). Here, we present an updated analysis of CDI in the tofacitinib UC clinical program. METHODS: CDI events were evaluated from 4 randomized, 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). 3 cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study) and Overall (pts receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3 or OLE studies; analyzed by pts receiving ≥ 1 dose of tofacitinib and predominant dose [PD; 5 or 10 mg BID based on average daily dose <15 mg or ≥ 15 mg, respectively]; data as of May 2019, database not locked). Proportions and incidence rates (unique pts with events per 100 pt-yrs [PY] of exposure) of CDI were evaluated. All pts underwent CDI screening; a positive test excluded pts from program entry. RESULTS: The Overall Cohort comprised 1,157 pts who received ≥ 1 dose of tofacitinib 5 or 10 mg BID, representing 2,581 PY of tofacitinib exposure and up to 6.8 yrs of treatment. CDI occurred in 3 pts in the Induction Cohort (PBO, n = 1; tofacitinib 10 mg BID, n = 2), 3 pts in the Maintenance Cohort (PBO, n = 3; CDI occurred 68, 81 and 98 days following initiation of PBO) and 9 pts in the Overall Cohort (PD tofacitinib 10 mg BID, n = 9; Table 1). Overall Cohort pts with CDI were mild (n = 4) or moderate (n = 5) in severity; 6 pts continued study treatment without interruption, 1 temporarily discontinued and 2 permanently discontinued. CDI resolved with treatment in 8 pts and CDI was still present in 1 pt at the time of study discontinuation. Two events were reported as serious AEs due to hospitalization. CONCLUSION: In the tofacitinib UC program, CDI rates among pts receiving tofacitinib have remained stable since the previous data cut (2) and are comparable to those reported for other advanced therapies (3).Table 1

S0787 An Update on the Analysis of Non-Melanoma Skin Cancer in the Tofacitinib Ulcerative Colitis Clinical Program as of May 2019

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We present an updated [1] analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical program as of May 2019. METHODS: NMSC events were evaluated from 3 randomized, placebo-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951] and 1 maintenance P3 study [NCT01458574]) and an ongoing, open-label, long-term extension (OLE) study (NCT01470612). Three cohorts were analyzed: Induction (P3 induction studies), Maintenance (P3 maintenance study), and Overall (patients [pts] receiving tofacitinib 5 or 10 mg twice daily [BID] in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose < 15 mg or ≥ 15 mg, respectively (82.4% of pts assigned PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis. RESULTS: 1,124 pts were evaluated for NMSC (2,576.4 PY of tofacitinib exposure; ≤ 6.8 years of treatment). NMSC events in the Induction and Maintenance Cohorts were previously reported (Table) [1]. NMSC occurred in 19 Overall Cohort pts (IR 0.73 [95% confidence interval (CI) 0.44, 1.13]; PD tofacitinib 5 mg BID, n = 3, IR 0.45 [0.09, 1.30]; PD tofacitinib 10 mg BID, n = 16, IR 0.82 [0.47, 1.34]) (Table); no new cases since Sep 2018 [1]. No NMSC was metastatic or led to discontinuation. Prior NMSC (hazard ratio [HR] 9.09 [95% CI 2.98, 27.73]), prior tumor necrosis factor inhibitor (TNFi) failure (HR 3.32 [1.08, 10.20]), and age (per 10-year increase, HR 2.03 [1.37, 3.02]) were significant risk factors for NMSC. CONCLUSION: NMSC events were infrequent with tofacitinib treatment and more likely to occur in pts with prior NMSC, prior TNFi failure, and with increasing age – known NMSC risk factors [2]. Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs were similar to those previously reported in the tofacitinib UC clinical program [1] and in pts with UC treated with biologics [3].Table 1

Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancy (Excluding Nonmelanoma Skin Cancer) Events Across the Ulcerative Colitis Clinical Program.

BackgroundTofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]).MethodsData (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated.ResultsThe overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46–1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time.ConclusionsIn the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.