DOP61 Tofacitinib, an oral, small-molecule Janus kinase inhibitor, in the treatment of ulcerative colitis: Analysis of an open-label, long-term extension study with up to 5.9 years of treatment

Abstract

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total Mayo score, plus ≥1-point RB subscore decrease or absolute RB subscore ≤1) at Month 2 of the OLE study were withdrawn.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

Outcomes of Tofacitinib Dose Reduction in Patients with Ulcerative Colitis in Stable Remission from the Randomised RIVETING Trial

“…Notably, all previously reported cases of venous thromboembolism from the OLE trial occurred in patients with a prior medical history that included risk factors for PE. 10,23 Therefore, the case of PE reported in RIVETING is the first case of deep vein thrombosis or PE recorded following long-term treatment with tofacitinib in the UC clinical program in a patient with no prior medical history that included risk factors for PE, beyond having UC itself which is a known risk factor for venous thromboembolic events. [24][25][26] It is also worth noting that although the patient"s endoscopic subscore remained at 0 throughout RIVETING, increases in both CRP and FCP were recorded, which may indicate increased inflammatory activity contributing to this event.…”

“…9 The tofacitinib Phase 3 clinical program also includes an ongoing, open-label, long-term extension [OLE] trial [OCTAVE Open, NCT01470612] with tofacitinib 5 and 10 mg twice daily [BID], which enrolled non-responders from OCTAVE Induction 1 and 2, and completers or treatment failures from OCTAVE Sustain. 10 Based on the OCTAVE program results, tofacitinib has been approved for patients with moderately to severely active UC at a dose of 10 mg BID for up to 16 weeks for induction of response, and at a dose of 5 mg BID for maintenance. A dose of 10 mg BID is also permitted during maintenance therapy for patients with loss of response on 5 mg BID maintenance therapy, but should be limited to the shortest duration possible and its use based on the risks and benefits to the individual patient.…”

Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure

“…3 Long-term extension (LTE) studies of tofacitinib included patients with RA, PsA, UC and PsO, with exposures up to 9.5, 3, 5.9 and 5.5 years, respectively, and demonstrated a consistent safety profile over time. [4][5][6][7] The objectives of this analysis were to provide a comparison of adverse events (AEs) of special interest from integrated pooled studies of the tofacitinib clinical programmes in RA, PsA, UC and PsO [8][9][10][11] ; to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events remain consistent across diseases after longer term exposure to tofacitinib; and to understand what factors might contribute to any differences.…”

Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis

“…Tofacitinib 5 and 10 mg twice daily have also demonstrated efficacy as maintenance therapy, vs placebo, in a phase 3, placebo‐controlled, 52‐week maintenance study (OCTAVE Sustain), 11 which enrolled responders from OCTAVE Induction 1 and 2. The long‐term safety and efficacy of tofacitinib 5 and 10 mg twice daily for patients with UC are being evaluated in an ongoing open‐label, long‐term extension study (OCTAVE Open) 12 …”

“…The long-term safety and efficacy of tofacitinib 5 and 10 mg twice daily for patients with UC are being evaluated in an ongoing open-label, long-term extension study (OCTAVE Open). 12 Population pharmacokinetic (PK) analysis provides insight into the disposition properties of a drug under investigation; characterizes sources and predictors of its PK variability, along with pharmacodynamic end points; and can assist in determining the optimal drug dose in the target patient population. In addition, population PK analysis also allows for further assessment of the relationships between systemic exposure and pharmacodynamic responses, which can facilitate various stages of drug development, and this provides valuable insights for regulatory review, approval, and labeling.…”