Effect of tofacitinib withdrawal and re-treatment on patient-reported outcomes: results from a Phase 3 study in patients with moderate to severe chronic plaque psoriasis.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. A Phase 3 withdrawal/re-treatment study (NCT01186744; OPT Retreatment) showed tofacitinib re-treatment was effective in patients with chronic plaque psoriasis. OBJECTIVES: To describe the effects of tofacitinib withdrawal/re-treatment on health-related quality of life (HRQoL) and disease symptoms measured by patient-reported outcomes (PROs). METHODS: The study was divided into initial treatment, treatment withdrawal, and re-treatment periods. Initial treatment: patients were randomized to receive tofacitinib 5 (n = 331) or 10 mg (n = 335) BID for 24 weeks. Treatment withdrawal: patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI) score from baseline and Physician's Global Assessment of 'clear'/'almost clear' at Week (W)24 received placebo (withdrawal) or the previous dose (continuous treatment). Re-treatment: at relapse (> 50% loss of W24 PASI response) or at W40, patients received their initial tofacitinib dose. PROs included: Dermatology Life Quality Index (DLQI), Itch Severity Item (ISI), Short Form-36 (SF-36) and Patient's Global Assessment (PtGA). RESULTS: After initial treatment with tofacitinib 5 and 10 mg BID, substantial and significant improvements were reported for mean DLQI (baseline: 12.6 and 12.6; W24: 5.1 and 2.6) and ISI (baseline: 6.7 and 6.9; W24: 2.9 and 1.6). Patients continuously treated with tofacitinib 5 and 10 mg BID maintained those improvements through Week 56 (DLQI: 3.0 and 2.1; ISI: 2.3 and 1.4). By W40, patients withdrawn from tofacitinib 5 and 10 mg BID showed worsening in DLQI (5.0 and 6.2) and ISI (3.7 and 4.0) scores; improvements were regained upon re-treatment (W56, DLQI: 3.4 and 2.4; ISI: 2.2 and 1.6). Similar results were reported for PtGA and SF-36. CONCLUSION: Continuous tofacitinib treatment provided sustained improvement in HRQoL and disease symptoms. Patients randomized to treatment withdrawal lost initial improvements. Upon re-treatment, improvements were recaptured to levels comparable to those seen with continuous treatment.

Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To compare outcomes following tofacitinib withdrawal with outcomes of continuation. METHODS: In this phase 3 study (NCT01186744), patients received tofacitinib 5 mg (n = 331) or 10 mg (n = 335) twice daily for 24 weeks. The patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) score from baseline and Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) received a placebo (withdrawal) or the previous dose. At relapse (> 50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose. RESULTS: Initial treatment: 33·5% and 55·2% achieved both PASI 75 and PGA responses with tofacitinib 5 and 10 mg twice daily, respectively, making them eligible for the treatment-withdrawal period. Withdrawal: 56·2%, 62·3%, 23·3% and 26·1% maintained PASI 75 responses with tofacitinib 5, 10 mg, placebo (5 mg) and placebo (10 mg) twice daily, respectively; 49·9%, 63·9%, 22·9% and 18·0% maintained PGA responses; and 92·3%, 93·0%, 32·8% and 42·9% did not relapse. Elevations in low-density lipoprotein-cholesterol levels following initial treatment (mean increase: 8·71 mg dL(-1) with 5 mg twice daily, 10·26 mg dL(-1) with 10 mg twice daily) were reversed upon withdrawal. Retreatment: 36·8% and 61·0% of patients who relapsed achieved PASI 75 responses with tofacitinib 5 or 10 mg after 16 weeks; 44·8% and 57·1% regained PGA responses. CONCLUSIONS: Patients who received continuous treatment maintained a response more effectively when compared with placebo recipients. Safety profiles were comparable in both the continuous treatment group and retreatment group. Of those patients who relapsed, up to 60% recaptured a response with tofacitinib.

Disruption of the IFN-gamma cytokine network in chronic lymphocytic leukemia contributes to resistance of leukemic B cells to apoptosis.

Recent evidence indicates that the slowly expanding population of CD5+ B cells that characterizes chronic lymphocytic leukemia (CLL) results primarily from defects in responses to cytokines that regulate apoptosis (e.g. I1-4, TGF-beta, IFN-alpha, IFN-gamma). We have now demonstrated not only that the enhanced anti-apoptotic effect of IFN-gamma on these neoplastic B cells is apparently mediated through increased levels of IFN-gamma receptors but also that there are increased numbers of IFN-gamma-expressing CD4 and CD8 T cells in these patients. This is the strongest evidence to date that multiple alterations in the IFN-gamma cytokine network contribute to the pathogenesis of CLL.

Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis.

PURPOSE: To determine the efficacy and safety of the neurokinin type 1 receptor antagonist CJ-11,974 for the control of high-dose cisplatin-induced emesis. PATIENTS AND METHODS: A double-blind, randomized, phase II design with a group sequential stopping rule was used in this study. Sixty-one patients with cancer who were receiving cisplatin at a dose of at least 100 mg/m2 for the first time were enrolled. All patients received granisetron 10 microg/kg and dexamethasone 20 mg intravenously 30 minutes before they were given cisplatin. Patients were randomly assigned to two groups: group 1 received CJ-11,974 100 mg, and group 2 received placebo orally 30 minutes before and 12 hours after cisplatin and then twice daily on days 2 through 5 after cisplatin. The primary end point was the percentage of patients who developed delayed emesis (emesis on the second to fifth days after cisplatin). RESULTS: Thirty patients were enrolled in group 1, and 31 patients were enrolled in group 2. Fifty-eight patients were assessable for efficacy. Complete control of emesis (expressed as the percentage of patients who had no emesis) was as follows: day 1, 85.7% (group 1) and 66.7% (group 2) (P = .090); days 2 through 5, 67.8% (group 1) and 36.6% (group 2) (P = .0425, adjusted); days 1 through 5, 64.3% (group 1) and 30% (group 2) (P = .009). Patients in group 1 experienced significantly less nausea than patients in group 2 on day 1 (P = .024). Treatment was well tolerated in both groups. CONCLUSION: We conclude from this exploratory phase II trial that CJ-11,974 is superior to placebo in controlling cisplatin-induced delayed emesis and may provide additive benefit in acute emesis and nausea control when combined with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. Additional larger trials are indicated to confirm the clinical value of CJ-11,974.