Mundayat, Rajiv

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were demonstrated in the OCTAVE clinical programme.1,2 Here, we present an analysis of the number and causes of UC-related hospitalisations during the OCTAVE clinical programme. Methods This descriptive analysis comprised patients (pts) hospitalised for UC who received placebo or tofacitinib 10 mg twice daily (BID) in OCTAVE Induction 1&2 (NCT01465763; NCT01458951)1, and pts who received placebo, or tofacitinib 5 or 10 mg BID in OCTAVE Sustain (NCT01458574)1, or ≥1 dose of tofacitinib in OCTAVE Open (NCT01470612)2; it includes data from pts with ≤7.8 years of tofacitinib exposure. We examined the demographic and clinical characteristics, proportions, causes and other aspects of UC-related hospitalisations in pts treated with placebo or tofacitinib in the OCTAVE clinical programme. Results Overall, 1139 pts with UC were included in this analysis. Demographic and disease characteristics of pts with UC-related hospitalisations were generally similar across treatment groups in each study; most pts were <40 years old, had pancolitis, a mean total Mayo score >8, prior treatment with oral corticosteroids and immunosuppressants (Table 1). Ninety-five pts had UC-related hospitalisations; of whom 92 had one UC-related hospitalisation and 3 pts were hospitalised twice (Table 2). In OCTAVE Induction 1&2, OCTAVE Sustain and OCTAVE Open, 2.1%, 1.0% and 6.6% of pts, respectively, had UC-related hospitalisations with tofacitinib 10 mg BID vs 1.0% and 2.9% of pts receiving tofacitinib 5 mg BID in OCTAVE Sustain and OCTAVE Open, and 3.4% and 4.0% of pts receiving placebo in OCTAVE Induction 1&2 and OCTAVE Sustain, respectively. UC-related hospitalisations did not lead to temporary treatment discontinuations in most pts (Table 2). The most frequent cause of UC-related hospitalisations in tofacitinib- and placebo-treated pts was non-surgical UC-related events (ie, UC flares; Table 2). Conclusion UC-related hospitalisations were infrequent in the OCTAVE clinical programme, and rates were generally lower than those reported in a real-world assessment of pts with UC treated with biological therapies.3 Most hospitalised pts were aged <40 years with severe disease and prior corticosteroid and immunosuppressant exposure. The most common cause of hospitalisation was non-surgical UC-related events. References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-1736. 2. Sandborn WJ et al. Aliment Pharmacol Ther 2022;55:464-478. 3. Bressler B et al. J Crohn’s Colitis 2021;15:1694-1706.

SummaryBackgroundObesity may affect efficacy and safety of biologic treatments for ulcerative colitis (UC). Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC.AimsTo assess efficacy and safety of tofacitinib in patients with UC, by baseline body mass index (BMI).MethodsThis post hoc analysis evaluated patients with UC receiving placebo or tofacitinib from the 8‐week OCTAVE Induction 1 and 2 (NCT01465763, NCT01458951) and 52‐week OCTAVE Sustain (NCT01458574) studies. Patients were stratified by BMI at OCTAVE Induction 1 and 2 baseline (<25, 25 to <30 and ≥30 kg/m2). Outcomes included remission, endoscopic improvement, clinical response, sustained steroid‐free remission, Inflammatory Bowel Disease Questionnaire total score and Short Form‐36 Health Survey scores. Adverse events were evaluated.ResultsAt Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain, higher proportions of patients receiving tofacitinib 5 or 10 mg twice daily (b.d.) achieved clinical response vs placebo, regardless of baseline BMI subgroup (all P < 0.05). Proportions of patients achieving efficacy endpoints were generally similar across BMI subgroups; in univariate and multivariate regression analyses, BMI was not a significant predictor (all P ≥ 0.05; univariate BMI [continuous] odds ratio for remission: 0.98 [95% confidence interval 0.95, 1.02]). There was no consistent trend between BMI and adverse events. Among patients receiving tofacitinib 10 mg b.d. in OCTAVE Induction 1 and 2, serious infections were numerically greater in the BMI ≥30 subgroup (3.2%) vs other subgroups (0.4%). Limitations included small patient numbers in the BMI ≥30 subgroup.ConclusionsEfficacy and safety of tofacitinib were similar in patients with UC regardless of baseline BMI.

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 Introduction Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disorder caused by the deposition of amyloid fibrils composed of misfolded transthyretin (TTR). ATTR amyloidosis may arise from mutations in TTR or from aggregation of wild-type TTR (ATTRwt). ATTR amyloidosis with predominantly symptoms of cardiomyopathy (ATTR-CM) includes both hereditary and wild-type forms of the disease. Purpose To describe clinical history and disease presentation in a large population of patients with wild-type ATTR-CM from the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. Methods Data from ATTRwt patients were extracted from THAOS (cut-off date: January 16, 2019) and demographic and clinical characteristics reported using descriptive statistics. Results There were 758 ATTRwt patients in THAOS (95% male). The majority of patients (69.3%) were in the United States, with the remainder in Italy (11.1%), Germany (7.3%), Spain (5.3%), and other countries (7.1%). Most patients (86.3%) were Caucasian, with 3.3% being of African Descent and 3.1% being of other races/ethnicities (7.4% missing data). The median (10–90th percentile) age at symptom onset was 69.7 (54.0–81.3) years and the median (10–90th percentile) time from symptom onset to diagnosis was 3.9 (0.1–17.8) years. Median (10–90th percentile) age at enrollment in THAOS was 76.4 (67.2–85.2) years. Nearly all subjects had either a cardiac (59.6%) or mixed cardiac and neurologic (36.5%) phenotype. At enrollment, 97.1% (577 of 594 patients assessed) had an abnormal ECG, with the prevalence of low voltage being 20.8% (115 of 552) and prevalence of left-ventricular hypertrophy being 2.1% (16 of 758). Atrial fibrillation was documented in 55% of patients (208 of 378). The mean (standard deviation [SD]) left-ventricular septum thickness was 17.5 (3.5) mm (n=505; 94.9% with thickness >12 mm) and mean (SD) left-ventricular ejection fraction (LVEF) was 48.3% (13.2) (n=511; 48.0% with LVEF <50.0%). Other signs and symptoms at enrollment were compatible with a sensory neuropathy in 54.2% of patients, autonomic neuropathy in 33.5% of patients, and motor neuropathy in 29.1% of patients. Gastrointestinal symptoms related to ATTR amyloidosis were present in 10.4% of patients. Conclusions Although patients with wild-type ATTR-CM tend to be older Caucasian men with a mostly cardiac disease phenotype, the clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype. Our findings show that ATTRwt should not be considered an exclusively cardiac disease and there is a need for both cardiologic and neurologic assessment of these patients. Further study is needed to determine if the non-cardiac manifestations are due to amyloidosis or more common causes in this older population. Acknowledgement/Funding This study was sponsored by Pfizer.