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

Arnab Mukherjee, Shinichi Tsuchiwata, Timothy Nicholas, Jack A Cook, Irene Modesto, Chinyu Su, Geert R D'Haens, William J Sandborn, Arnab Mukherjee, Shinichi Tsuchiwata, Timothy Nicholas, Jack A Cook, Irene Modesto, Chinyu Su, Geert R D'Haens, William J Sandborn

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.

Conflict of interest statement

A.M., S.T., T.N., J.A.C., I.M., and C.S. are employees and stockholders of Pfizer Inc. G.R.D’H. has served as an advisor for AbbVie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol‐Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Dr. Falk Pharma, Engene, Ferring, Galapagos, Gilead Sciences, GSK, Hospira, Johnson and Johnson, Medimetrics, Millennium/Takeda, Mitsubishi Pharma, MSD, Mundipharma, Novo Nordisk, Pfizer Inc, Prometheus Laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, TiGenix, Tillotts, Topivert, Versant, and Vifor; and has received speaker fees from AbbVie, Ferring, Johnson and Johnson, Millennium/Takeda, MSD, Mundipharma, Norgine, Pfizer Inc, Shire, Tillotts, and Vifor. W.J.S. reports grants, personal fees, and non‐financial support from Pfizer Inc during the conduct of the study; research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GSK, Janssen, Lilly, Pfizer Inc, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, AdMIRx, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), BeiGene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol‐Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer Inc, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vedanta Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, and Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Prometheus Laboratories Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Biosciences; and employment at Shoreline Biosciences. W.J.S.’s spouse reports consulting fees from Iveric Bio, Oppilan Pharma, and Prometheus Laboratories; stock options from Iveric Bio, Oppilan Pharma, Prometheus Biosciences, Prometheus Laboratories, Ventyx Biosciences, and Vimalan Biosciences; and stock from Progenity, Prometheus Biosciences, Ventyx Biosciences, and Vimalan Biosciences.

© 2022 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
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 Cavg 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. Cavg, average concentration during dosing interval; CI, confidence interval.
Figure 2
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 Cavg 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 Cavg 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. Cavg, average concentration during dosing interval; CI, confidence interval; E‐R, exposure‐response; PK, pharmacokinetic; TNFi, tumor necrosis factor inhibitor.
Figure 3
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 Cavg values were 16.8 and 33.6 ng/mL for the tofacitinib 5 and 10 mg b.i.d. groups, respectively. Cavg, average concentration during dosing interval; CI, confidence interval.

References

    1. Fakhoury, M. , Negrulj, R. , Mooranian, A. & Al‐Salami, H. Inflammatory bowel disease: clinical aspects and treatments. J. Inflamm. Res. 7, 113–120 (2014).
    1. Ungaro, R. , Mehandru, S. , Allen, P.B. , Peyrin‐Biroulet, L. & Colombel, J.‐F. Ulcerative colitis. Lancet 389, 1756–1770 (2017).
    1. Rubin, D.T. , Ananthakrishnan, A.N. , Siegel, C.A. , Sauer, B.G. & Long, M.D. ACG clinical guideline: ulcerative colitis in adults. Am. J. Gastroenterol. 114, 384–413 (2019).
    1. Harbord, M. et al. Third European evidence‐based consensus on diagnosis and management of ulcerative colitis. Part 2: current management. J. Crohns Colitis 11, 769–784 (2017).
    1. Ochsenkühn, T. , Tillack, C. , Szokodi, D. , Janelidze, S. & Schnitzler, F. Clinical outcomes with ustekinumab as rescue treatment in therapy‐refractory or therapy‐intolerant ulcerative colitis. United European Gastroenterol. J. 8, 91–98 (2020).
    1. Feagan, B.G. et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double‐blind, randomised, placebo‐controlled trial. Lancet 397, 2372–2384 (2021).
    1. Sandborn, W.J. et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 367, 616–624 (2012).
    1. Sandborn, W.J. et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 376, 1723–1736 (2017).
    1. European Medicines Agency Xeljanz® (tofacitinib): summary of product characteristics < (2020). Accessed September 1, 2021.
    1. Pfizer Inc Xeljanz® (tofacitinib): s of prescribing information < (2020). Accessed October 14, 2021.
    1. Vong, C. et al. Population pharmacokinetics of tofacitinib in patients with moderate to severe ulcerative colitis. Clin. Pharmacol. Drug Dev. 10, 229–240 (2021).
    1. Mukherjee, A. et al. Exposure‐response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: results from a dose‐ranging phase 2 trial. Br. J. Clin. Pharmacol. 84, 1136–1145 (2018).
    1. Schroeder, K.W. , Tremaine, W.J. & Ilstrup, D.M. Coated oral 5‐aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N. Engl. J. Med. 317, 1625–1629 (1987).
    1. Lichtenstein, G.R. et al. Baseline albumin level is not a significant predictor of tofacitinib efficacy in patients with ulcerative colitis: results of multivariate exposure‐response analysis. Am. J. Gastroenterol. 113, S354–S355 (2018).
    1. Lamba, M. et al. Model‐informed development and registration of a once‐daily regimen of extended‐release tofacitinib. Clin. Pharmacol. Ther. 101, 745–753 (2017).
    1. Mukherjee, A. et al. Pharmacokinetics and exposure‐response of tofacitinib in a Phase 3 maintenance study in ulcerative colitis patients. J. Crohns Colitis 11(Suppl 1), S69–S70 (2017).
    1. Dubinsky, M.C. et al. Efficacy of tofacitinib in patients with ulcerative colitis by prior tumor necrosis factor inhibitor treatment status: results from OCTAVE induction and maintenance studies. Am. J. Gastroenterol. 112, S354 (2017).
    1. Sandborn, W.J. et al. Efficacy and safety of tofacitinib in ulcerative colitis based on prior tumor necrosis factor inhibitor failure status. Clin. Gastroenterol. Hepatol. 20, 591–601 (2022).
    1. Peyrin‐Biroulet, L. et al. Efficacy of filgotinib in patients with ulcerative colitis by line of therapy in the phase 2b/3 SELECTION trial. J. Crohns Colitis 15(Suppl 1), S024–S026 (2021).
    1. Rosario, M. et al. Exposure‐efficacy relationships for vedolizumab induction therapy in patients with ulcerative colitis or Crohn's disease. J. Crohns Colitis 11, 921–929 (2017).
    1. Xu, Y. et al. Population pharmacokinetics and exposure‐response modeling analyses of ustekinumab in adults with moderately to severely active ulcerative colitis. J. Clin. Pharmacol. 60, 889–902 (2020).
    1. Lawendy, N. et al. Effect of CP‐690,550, an orally active Janus kinase inhibitor, on renal function in healthy adult volunteers. J. Clin. Pharmacol. 49, 423–429 (2009).
    1. Hemperly, A. & Vande Casteele, N. Clinical pharmacokinetics and pharmacodynamics of infliximab in the treatment of inflammatory bowel disease. Clin. Pharmacokinet. 57, 929–942 (2018).
    1. Weisman, M.H. et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti‐tumor necrosis factor‐alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin. Ther. 25, 1700–1721 (2003).
    1. Zhuang, Y. et al. Golimumab pharmacokinetics after repeated subcutaneous and intravenous administrations in patients with rheumatoid arthritis and the effect of concomitant methotrexate: an open‐label, randomized study. Clin. Ther. 34, 77–90 (2012).
    1. Rutgeerts, P. , Vermeire, S. & Van Assche, G. Predicting the response to infliximab from trough serum levels. Gut 59, 7–8 (2010).
    1. Bortlik, M. et al. Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease. J. Crohns Colitis 7, 736–743 (2013).
    1. Roblin, X. et al. Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases. Clin. Gastroenterol. Hepatol. 12, 80–84 (2014).
    1. Adedokun, O.J. et al. Pharmacokinetics and exposure‐response relationship of golimumab in patients with moderately‐to‐severely active ulcerative colitis: results from phase 2/3 PURSUIT induction and maintenance studies. J. Crohns Colitis 11, 35–46 (2017).
    1. Lee, S.D. et al. Therapeutic drug monitoring for current and investigational inflammatory bowel disease treatments. J. Clin. Gastroenterol. 55, 195–206 (2021).
    1. Hindryckx, P. et al. Review article: dose optimisation of infliximab for acute severe ulcerative colitis. Aliment. Pharmacol. Ther. 45, 617–630 (2017).

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