Huaming Tan

Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study.

Background  Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.

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

Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate‐to‐severe plaque psoriasis.

Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, improves patient-reported outcomes in a phase 2b, randomized, double-blind, placebo-controlled study in patients with moderate-to-severe psoriasis

Psoriasis is a chronic, inflammatory skin disease with a significant impact on health–related quality of life (HRQoL). Tofacitinib (CP‐690,550) is a novel, oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator.

Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment

The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210).

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: Long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study

BACKGROUND Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. OBJECTIVES We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. METHODS Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. RESULTS At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. LIMITATIONS There was no dose comparison beyond week 52. CONCLUSIONS Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study

BACKGROUND Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. OBJECTIVE We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis. METHODS Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67(+) keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT](+) nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray. RESULTS In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1(+) cells/μm(2); day 1, median of 332 pSTAT1(+) cells/μm(2); and nonlesional, median of 155 pSTAT1(+) cells/μm(2)). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression. CONCLUSIONS Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway.

Tofacitinib versus etanercept or placebo in patients with moderate to severe chronic plaque psoriasis: patient-reported outcomes from a Phase 3 study

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. Psoriasis impacts on physical and psychological well‐being; improvements in health‐related quality of life (HRQoL) with etanercept in psoriasis are well documented.

Herpes zoster in psoriasis patients treated with tofacitinib

Background Tofacitinib is an oral Janus kinase (JAK) inhibitor. Immunomodulatory therapies can increase the risk for herpes zoster (HZ) in patients with psoriasis. Objective To evaluate the relationship between tofacitinib use and HZ risk. Methods We used phases 2 and 3 and long‐term extension (LTE) data from the tofacitinib development program in psoriasis to calculate HZ incidence rates (IR; events per 100 patient‐years); potential HZ risk factors were evaluated using Cox‐proportional hazard models. Results One hundred thirty (3.6%) patients on tofacitinib (IR 2.55), no patients on placebo, and 2 using etanercept (IR 2.68) developed HZ. Nine patients (7%) were hospitalized, and 8 (6%) had multidermatomal HZ; no encephalitis, visceral involvement, or deaths occurred. In total, 121 (93%) patients on tofacitinib continued or resumed use after HZ. HZ risk factors included Asian descent (hazard ratio [HR] 2.92), using tofacitinib 10 mg twice daily (vs 5 mg twice daily; HR 1.72), prior use of biologics (HR 1.72), and older age (HR 1.30). Limitations Generalizability to other psoriasis populations might be limited. The effect of HZ vaccination was not studied. Conclusion Tofacitinib is associated with increased HZ risk relative to placebo. Asian race, increasing age, higher dose, and prior biologic exposure are associated with heightened risk.

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

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.

Dose Response and Pharmacokinetics of Tofacitinib (CP‐690,550), an Oral Janus Kinase Inhibitor, in the Treatment of Chronic Plaque Psoriasis

Longitudinal nonlinear mixed effects modeling was used to characterize the dose–response profile of tofacitinib using data from a placebo‐controlled dose‐ranging study, where tofacitinib 2, 5, and 15 mg twice daily (b.i.d.) were evaluated for plaque psoriasis treatment. Bayesian estimation was applied with prior information derived from the literature: nonclinical and clinical data in psoriasis, as well as other indications. The probability to achieve a certain target effect associated with a given dose was calculated from the posterior samples. On the basis of these probabilities along with safety considerations, tofacitinib 5 and 10 mg b.i.d. were selected for further testing in confirmatory phase III clinical trials. Pharmacokinetics in patients with psoriasis was characterized using a population‐based modeling approach, and body weight was identified as an important covariate. A subgroup analysis suggested reduced efficacy of tofacitinib with increasing body weight; however, it is unclear whether this trend could be explained by systemic exposure alone.