Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Abstract

ObjectiveTofacitinib 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).DesignWe 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.Results180/280 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.ConclusionsPrimary 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.Trial registration numbersNCT01393626 and NCT01393899.

Long‐term safety and tolerability of oral tofacitinib in patients with Crohn’s disease: results from a phase 2, open‐label, 48‐week extension study

“…Rates of adverse events were generally similar for patients receiving tofacitinib 5 and 10 mg b.d. and were consistent with the previous 26‐week maintenance study . In the maintenance study, Crohn's disease worsening was also the most frequently occurring adverse event, although rates were lower than those reported here.…”

“…After 26 weeks of maintenance therapy, a higher proportion of patients receiving tofacitinib 10 mg twice daily (b.d.) showed clinical response‐100 (defined as a CDAI score reduction of at least 100 points from baseline) or remission vs placebo, although these differences were also not statistically significant …”

“…It has also been investigated for Crohn's disease. The efficacy and safety of tofacitinib for inducing and maintaining clinical remission (defined as Crohn's disease activity index [CDAI] score <150) in patients with moderate‐to‐severe Crohn's disease have previously been investigated in two phase 2b studies . These induction and maintenance studies showed a modest treatment effect of tofacitinib compared with placebo, although the primary induction efficacy endpoint of clinical remission at week 8 was not significantly different from placebo.…”

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…In patients with moderately to severely active UC, tofacitinib was found to be more effective as induction and maintenance therapy than placebo and is now approved for this disease . Curiously, efficacy in CD has been less consistent . The mechanisms underlying the divergent effects are not known, but this is another example where targeted therapies may have the potential for revealing pathogenetic mechanisms, assuming that this is a consistent finding with other jakinibs.…”

Targeted therapy of inflammatory bowel diseases: realities and prospects

“…Несмотря на обна-деживающие результаты применения данного препарата у пациентов с ЯК, данные о его эффективности при БК огра-ниченны. Недавно завершенное РКИ II фазы выявило положительную тенденцию при применении тофациниба у пациентов с БК, однако по сравнению с плацебо она ока-залась статистически незначимой [46]. Использование другого ингибитора JAK -филготиниба у пациентов с БК в рамках РКИ II фазы оказалось в два раза эффективнее плацебо в индукции клинической ремиссии заболевания к 10-й неделе, однако значимой разницы в эндоскопиче-ском ответе на лечение отмечено не было [47].…”