Janus kinases (JAKs), a family of intracellular proteins, consist of JAK 1, 2, and 3 and the related kinase tyrosine kinase 2 (TYK2). Several JAK inhibitors were developed as therapy for immune-mediated diseases like rheumatoid arthritis, IBD, and psoriasis. Some compounds with JAK inhibitor activity have been tested for efficacy as potential UC treatments. They are small molecules characterized by oral administration, short serum half-life, intracellular target, and non-antigenicity. The results of JAK treatment for UC are summarized in Table 1.
Tofacitinib, a non-selective JAK inhibitor, has recently been approved in Europe for adult patients with moderate to severe active UC who responded poorly, lost response, or were intolerant to either conventional therapy or a biologic agent. A few years ago, a phase II clinical trial demonstrated for the first time that tofacitinib was effective in UC. This trial was conducted on 194 patients with moderate to severe UC who had not responded to conventional therapy, anti-TNF agents or a combined approach. Tofacitinib at doses of 0.5, 3, 10 or 15 mg was administered twice daily vs placebo for 8 wk. Patients displayed an excellent clinical response, with the highest dose group having an almost 78% response rate. The endoscopic response was defined as a decrease of at least 1 from baseline in the endoscopy subscore, and endoscopic remission was defined as an endoscopic subscore of 0. At 8 wk, endoscopic remission occurred in 1/48 patients (2%) receiving placebo, compared with 3/31 (10%) receiving 0.5 mg of tofacitinib (P = 0.14), 6/33 (18%) receiving 3 mg of tofacitinib (P = 0.01), 10/33 (30%) receiving 10 mg of tofacitinib (P < 0.001), and 13/49 (27%) receiving 15 mg of tofacitinib (P < 0.001). The post hoc analysis showed that median fecal calprotectin (FCP) concentrations at week 8 were significantly lower (P < 0.001) in responders than in non-responders (P < 0.001) with respect to endoscopic remission (44 mg/kg vs 489 mg/kg) and MH (127 mg/kg vs 753 mg/kg). Moreover, an FCP cut-off value of 150 mg/kg displayed the highest sensitivity and specificity for clinical (0.68 and 0.79, kappa = 0.44) and endoscopic (0.79 and 0.75, kappa = 0.38) remission. The authors concluded that daily fluctuations in FCP concentrations might account for the low agreement between FCP and endoscopic remission. In addition, residual inflammation might still persist histologically despite MH and endoscopic remission. Since safety concerns (hyperlipidemia and viral infections) emerged for patients receiving the highest dose, the US Food and Drug Administration subsequently authorized only the 10 mg dose for clinical development. Consequently, the most recent OCTAVE (Oral Clinical Trials for tofAcitinib in ulceratiVE colitis ) trials on tofacitinib induction were conducted using a 10 mg dose twice daily.
OCTAVE trials: Three multi-centre, randomized, double-blind, placebo-controlled trials (OCTAVE Induction 1; OCTAVE Induction 2; and OCTAVE Sustain) were conducted on moderate to severe UC. In the OCTAVE Induction 1 and 2 trials, 1139 eligible patients were randomly assigned to induction therapy with oral tofacitinib at a dose of 10 mg twice daily or placebo for 8 wk. The primary endpoint was remission at the end of the study, and the key secondary endpoint was MH (Mayo endoscopic subscore of 0 or 1) at 8 wk. Of note, endoscopic results were centrally assessed by a blinded observer, a methodological advance that has been adopted in recent UC studies. In the OCTAVE Induction 1 trial, 18.5% of patients receiving tofacitinib achieved the primary end point, i.e., remission at 8 wk compared with 8.2% of the placebo group (P = 0.007). In the OCTAVE Induction 2 trial, remission rates were 16.6% vs 3.6% (P < 0.001). Both trials displayed similar results for the key secondary endpoint. MH was achieved in 31.3% (OCTAVE 1) and 28.4% (OCTAVE 2) patients receiving tofacitinib vs 15.6% and 11.6% in the placebo groups, respectively (P < 0.001 for both comparisons). Although these success rates may appear unimpressive, it should be emphasized that both study populations were highly treatment-refractory. All patients had, in fact, failed to respond to conventional therapies for UC, including TNF-blockers, and approximately half were receiving corticosteroids at baseline. Nevertheless, in subgroup analyses, a consistent treatment effect of tofacitinib was observed in anti-TNF naïve and anti-TNF exposed patients.
In the OCTAVE Sustain trial, 593 patients who had completed the OCTAVE Induction 1 or 2 trial and had responded clinically to induction therapy were assigned to tofacitinib maintenance therapy (5 or 10 mg twice daily) or placebo for 52 wk. MH, a key secondary end point, occurred in significantly more patients than placebo in both groups. Specifically, MH was observed in 74/198 patients (37.4%) in the 5 mg group and in 90/ 197 (45.7%) in the 10 mg group, vs 26/198 (13.1%) in the placebo cohort (P < 0.001 for both comparisons). At week 24, MH was observed in 43.9% of the 5 mg group and in 46.2% of the 10 mg group vs 17.2% of the placebo group. Also at week 24, MH was maintained in 52.4% of participants with MH at baseline who received the 5 mg tofacitinb dose and in 66.3% who received 10 mg tofacitinb, compared with 21.8% in the placebo group (P < 0.001). Endoscopic remission, defined as an endoscopic subscore of 0, was another end-point. After 24 and 52 wk, it was observed in 16.2% and 14.6% of the 5 mg tofacitinib group and in 12.2% and 16.8% of the 10 mg tofacitinib group, respectively, vs 4% of placebo patients. Sustained endoscopic remission, defined as responses at both week 24 and 52, was 6.1% and 5.1% in the 5 mg and the 10 mg tofacitinib groups, respectively.
In post-hoc analyses of East Asian patients with active UC who were enrolled in global phase 3 induction and maintenance studies, twice daily doses of 10 mg oral tofacitinib induced MH with greater efficacy than placebo. At week 8, 10 mg tofacitinib was associated with a 24.2% response rate vs 7.7% with placebo. Similarly, MH was achieved at week 52 in 45.5% of patients receiving 5 mg tofacitinib, and in 57.1% of those given 10 mg twice daily of tofacitinib vs 20.0% receiving placebo.
An ongoing, open-label, long-term extension study (OCTAVE Open) included non-responders from OCTAVE Induction 1 and 2, and patients who had completed or experienced treatment failure in OCTAVE Sustain. This trial was conducted in a subpopulation of 58 patients who achieved clinical response following 8 wk induction therapy with 10 mg twice daily tofacitinib. The patients entered OCTAVE Sustain receiving 5 mg twice daily tofacitinib, but experienced treatment failure between week 8 and 52. In the OCTAVE Open, these patients were escalated to 10 mg tofacitinib twice daily, which induced MH in 41.4% and 60.4% patients at months 2 and 12, respectively, compared with baseline (5.2%).
Peficitinib, a JAK1, JAK2, and JAK3 oral inhibitor, has an in vitro potency that is approximately 6- to 7-fold greater for JAK3 than for JAK1 and JAK2. In a phase 2b randomized, double-blind, placebo-controlled, dose-ranging trial, its efficacy and safety were evaluated in 219 patients with moderate-to-severe UC. Patients were equally randomized to receive oral placebo or 25, 75 or 150 mg peficitinib once daily, or 75 mg peficitinib twice daily. At week 8, patients were assessed for clinical response, and MH was one of the secondary endpoints. The Mayo endoscopic subscores were assigned by the local reader (blinded to treatment assignment) and the central reader (blinded to treatment assignment and clinical examination). Few patients achieved normal or inactive mucosal disease (endoscopy subscore of 0). At week 8, MH was observed in 20.5% (25 mg daily), 29.5% (75 mg daily), 45.5% (150 mg daily,) 36.4% (75 mg twice daily) vs 18.6% of patients (placebo). While no dose-response of peficitinib was demonstrated in patients with moderate-to-severe UC, evidence of efficacy in achieving MH was suggested at doses ≥ 75 mg daily vs placebo.