Exposure-Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies

Abstract

Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure-response (E-R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain). Induction studies included 1,355 patients (tofacitinib 0.5, 3, 10, or 15 mg b.i.d. or placebo). The maintenance study included 592 patients (tofacitinib 5 or 10 mg b.i.d. or placebo). E-R models, including induction patients predicted placebo-adjusted remission rates of 6.4% and 12.7% at week 8 for tofacitinib 5 and 10 mg b.i.d., respectively; corresponding rates in patients without prior tumor necrosis factor inhibitor (TNFi) failure were 12.8% and 20.4%. Estimates to achieve/maintain remission at week 52 of maintenance were 29% and 18% (tofacitinib 5 mg b.i.d.), and 41% and 26% (tofacitinib 10 mg b.i.d.), for patients in remission or not following induction, respectively. During maintenance, patients with prior TNFi failure had lower probability of remission on 5 mg b.i.d. (24.9%) than 10 mg b.i.d. (35.0%). Results indicated tofacitinib 10 mg b.i.d. was an appropriate induction dose but suggested efficacy with 5 mg b.i.d. in patients without prior TNFi failure. Tofacitinib 5 mg b.i.d. was efficacious for maintenance, although patients with prior TNFi failure might see additional benefit on 10 mg b.i.d. Per product labeling, recommended tofacitinib induction dose is 10 mg b.i.d., then maintenance at 5 mg b.i.d. For patients who lose response during maintenance, 10 mg b.i.d. may be considered, limited to the shortest duration. Clinicaltrials.gov: NCT00787202; NCT01465763; NCT01458951; and NCT01458574.

Figure 1

Probability of (a) remission and (b) endoscopic improvement at week 8 in OCTAVE Induction 1 and 2. The solid lines represent model‐predicted probability and the shaded areas represent the 95% CI. Observed probabilities by dose (placebo, tofacitinib 10 mg b.i.d., and tofacitinib 15 mg b.i.d.; black symbols) are plotted at the geometric mean of individual C_avg values for tofacitinib 10 mg b.i.d. (33.6 ng/mL) and 15 mg b.i.d. (50.4 ng/mL), error bars represent 95% CI. C_avg, average concentration during dosing interval; CI, confidence interval.

Figure 2

Observed (symbols) and model predicted (solid line and shaded area) remission rate based on E‐R analysis of pooled phase II and phase III induction data in the subpopulation of patients without prior TNFi failure. Pooled data are displayed separately for phase II and phase III. The solid lines represent model‐predicted probability and the shaded areas represent the 95% CI. The vertical dashed lines indicate median C_avg for tofacitinib 5 mg b.i.d. (16.8 ng/mL), derived from the dose‐normalized, individual empirical Bayes estimates obtained from the population PK model. Observed probabilities by dose are plotted at the geometric mean of individual C_avg values at tofacitinib 0.5 mg b.i.d. (1.68 ng/mL), 3 mg b.i.d. (10.08 ng/mL), 10 mg b.i.d. (33.6 ng/mL), and 15 mg b.i.d. (50.4 ng/mL), error bars represent 95% CI. C_avg, average concentration during dosing interval; CI, confidence interval; E‐R, exposure‐response; PK, pharmacokinetic; TNFi, tumor necrosis factor inhibitor.

Figure 3

Probability of (a) remission, (b) sustained steroid‐free remission, and (c) endoscopic improvement at week 52 by baseline status in OCTAVE Sustain, using the basic Markov transition model. The solid lines represent model‐predicted probability, the shaded area represents 95% prediction interval and the error bars represent 95% CI. The symbols represent the observed ratio for tofacitinib 5 mg b.i.d., tofacitinib 10 mg b.i.d., and placebo. Typical C_avg values were 16.8 and 33.6 ng/mL for the tofacitinib 5 and 10 mg b.i.d. groups, respectively. C_avg, average concentration during dosing interval; CI, confidence interval.