Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated ...patients with moderate to severe UC.
Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years’ exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events.
In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4–6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2–12.2) vs placebo (IR, 1.0, 95% CI, 0.0–5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1–0.6); serious infections, 2.0 (95% CI, 1.4–2.8); opportunistic infections, 1.3 (95% CI, 0.8–2.0); herpes zoster infection, 4.1 (95% CI, 3.1–5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3–1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3–1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1–0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0–0.5).
In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.
Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in ...patients with moderate-to-severe Crohn's disease (CD).
We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study.
180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments.
Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib.
NCT01393626 and NCT01393899.
Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We analyzed inflammation, lipid concentrations, and incidence rates of major adverse ...cardiovascular (CV) events (MACEs) in patients who received tofacitinib in worldwide studies.
We collected data from 1157 patients who participated in 3 8-week induction studies (1 phase-2 study and 2 phase-3 studies; patients received tofacitinib 10 mg twice daily or placebo), a 52-week phase-3 maintenance study of responders (patients received tofacitinib 5 or 10 mg twice daily or placebo), and an ongoing long-term extension study of patients who did and did not respond to induction or maintenance therapy (patients received tofacitinib 5 or 10 mg twice daily). Lipid concentrations were assessed from induction baseline to week 61 (week 52 of maintenance therapy). We calculated MACE incidence rates (patients with ≥1 event per 100 patient-years of exposure) and Reynolds risk score (RRS; a composite score used to determine CV risk) for patients given tofacitinib vs placebo.
The mean RRS was <5% at baseline and week 8 of treatment with tofacitinib. At week 8, there were greater increases from baseline in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol in patients given tofacitinib compared with placebo. There were correlations between reduced levels of high-sensitivity C-reactive protein and increased serum concentrations of lipid in patients given tofacitinib or placebo (P < .001). Lipid concentrations were increased in patients given tofacitinib vs patients given placebo through week 61. Overall, ratios of low-density lipoprotein cholesterol to HDL-c and total cholesterol to HDL-c did not change significantly over the 61-week period. Four MACEs were reported; the incidence rate was 0.24 (95% CI, 0.07–0.62) and 3 of these patients had 4 or more CV risk factors.
In an analysis of data from 5 trials of patients with UC who received tofacitinib, we found reversible increases in lipids with treatment and inverse correlations with reduced levels of high-sensitivity C-reactive protein. We did not find clinically meaningful changes in lipid ratios or RRS. MACEs were infrequent and not dose-related. Clinicaltrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612)
Summary
Background
Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease.
Aims
This 48‐week open‐label extension study primarily ...investigated long‐term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease.
Methods
Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in remission (Crohn's disease activity index <150) at baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. A single dose adjustment was allowed after 8 weeks’ fixed, open‐label treatment.
Results
Sixty‐two patients received tofacitinib 5 mg b.d.; 88 received 10 mg b.d. Both groups had similar rates of adverse events and serious infections. Crohn's disease worsening was the most frequent adverse event for tofacitinib 5 (33.9%) and 10 mg b.d. (19.3%). Patients not in remission at baseline, receiving 10 mg b.d., had higher rates of serious adverse events (19.3%) and discontinuation attributed to insufficient clinical response (30.7%) vs 5 mg b.d. (8.1% and 9.7%, respectively). At week 48, of patients with baseline remission receiving 5 mg b.d., 87.9% maintained remission and 75.0% sustained remission as observed (46.8% and 38.7%, respectively, by non‐responder imputation). Study design prevented between‐dose efficacy comparisons.
Conclusions
No new safety signals emerged. Although both doses showed generally similar safety outcomes for overall adverse events, serious adverse events were more frequent for tofacitinib 10 than 5 mg b.d. Discontinuation due to insufficient clinical response was lower among patients in remission at baseline. ClinicalTrials.gov: NCT01470599.
Abstract
Background
Tofacitinib is an oral, small molecule Janus kinase (JAK) inhibitor that is being investigated for IBD. In a recent trial of Crohn's disease (CD) patients (pts), small treatment ...effects for tofacitinib vs placebo (PBO) were noted using CD Activity Index (CDAI)-based enrollment criteria without endoscopic scoring (1). We report post-hoc analyses of efficacy endpoints (CDAI-based and composite outcomes) in subgroups based on objective baseline (BL) criteria of disease activity.
Methods
In a randomized, double-blind, PBO-controlled multicenter Phase 2b trial (NCT01393626), pts with moderate to severe CD (CDAI 220-450) received PBO, tofacitinib 5 or 10mg twice daily (BID) for 8 weeks. Clinical remission (CDAI <150), clinical response 100 (≥100 CDAI reduction from BL), composite remission (remission and ≥50% C-reactive protein CRP or fecal calprotectin FCP reduction from BL) and composite response (CDAI-100 response and ≥50% CRP or FCP reduction from BL) were analyzed at Week 8, by subgroups defined by BL simple endoscopic score (SES) <11 (median 11; local read), SES ≥11 or biomarkers (CRP ≥5mg/L or FCP ≥250mg/kg).
Results
In pts with BL SES ≥11, significantly higher proportions achieved remission, composite remission and composite response with tofacitinib vs PBO (all p<0.05 except clinical remission with tofacitinib 5mg BID; Table). Observations were similar in pts with BL CRP ≥5 or FCP ≥250. Pts with BL SES <11 had significantly higher rates of composite remission and composite response with tofacitinib vs PBO (all p<0.05 except composite remission with tofacitinib 5mg BID).
Conclusion
Increased proportions of pts were in remission and achieved composite remission and composite response with tofacitinib vs PBO, when analyses were done using more objective BL criteria of active disease than simple measure of CDAI. Results from these post-hoc analyses support further investigation of JAK inhibition in CD.
1. Panés J, et al. Gut 2017;66:1049-59
PDF
