Myelopreservation with Trilaciclib in recurrent advanced ovarian cancer: a case report.

Ovarian cancer is a prevalent malignant tumor of the female reproductive system, often remaining concealed until it reaches an advanced stage. The standard treatment protocol includes cytoreductive surgery for ovarian cancer plus postoperative consolidation chemotherapy and maintenance therapy, although it carries a high recurrence rate. During the treatment period, chemotherapy can lead to bone marrow suppression, a condition known as Chemotherapy-Induced Myelosuppression (CIM). This suppression may necessitate dose reduction or chemotherapy treatment cycle delay. In severe cases, CIM can result in infection, fever, and potential harm to the patient's life. Here, we report a case of a female patient with ovarian malignant tumor of biochemical recurrence who treated with chemotherapy combined with Trilaciclib, following previous perioperative chemotherapy with occurrence of severe CIM. It involves an intravenous injection of Trilaciclib before chemotherapy, which significantly abates the side effects of chemotherapy, reduces the occurrence of severe CIM, improves the patients' quality of life, and decreases the economic burden of hospitalization. We hope that this retrospective analysis of the case may serve as a reference in preventing and treating severe CIM during chemotherapy in some patients with malignant tumors, ultimately benefiting more patients with tumors.

Subgroup Analysis of Crisaborole for Mild-to-Moderate Atopic Dermatitis in Children Aged 2 to < 18 Years.

OBJECTIVES: This post hoc analysis of pooled data from two phase III studies (AD-301: NCT02118766; AD-302: NCT02118792) explored the efficacy and safety of crisaborole ointment, 2%, a nonsteroidal phosphodiesterase 4 inhibitor, for the treatment of mild-to-moderate atopic dermatitis (AD) in pediatric patients (aged 2 to < 18 years) only, stratified by baseline characteristics. METHODS: Pediatric patients with mild or moderate AD per Investigator's Static Global Assessment (ISGA) and percentage of treatable body surface area (%BSA) ≥ 5 at baseline were assessed. Crisaborole or vehicle (2:1 randomization ratio) was applied twice daily for 28 days. Of the 1313 pediatric patients included in this study, 874 received crisaborole and 439 received vehicle. ISGA success was defined as clear (0) or almost clear (1) with ≥ 2-grade improvement from baseline. Efficacy and safety were stratified by age group, sex, baseline ISGA, baseline %BSA per published severity strata, and prior AD therapy. RESULTS: Overall, the proportions of crisaborole-treated and vehicle-treated pediatric patients with ISGA success at week 4 were 32.5 and 21.5%, respectively. ISGA success rates at day 29 (week 4) were generally higher in crisaborole-treated (21.9-38.1%) than vehicle-treated (15.7-26.9%) patients across subgroups. Rates of treatment-related application site pain were 2.4-10.1% for crisaborole-treated patients and 0.6-2.2% for vehicle-treated patients across subgroups. No new safety concerns were noted in any patient subgroup. CONCLUSION: Crisaborole improved global disease severity and was reasonably well tolerated across all pediatric baseline characteristic subgroups. Application site discomfort was greater with crisaborole than with vehicle, but few patients discontinued treatment. GOV REGISTRATION NUMBERS: NCT02118766; NCT02118792 (registration date: April 21, 2014).

Crisaborole is an ointment approved for the treatment of mild-to-moderate eczema. In two phase III clinical trials, eczema improved after 28 days of crisaborole use in patients aged ≥ 2 years. Patients with eczema rashes used crisaborole or plain ointment twice a day for 28 days. The clinical trials excluded patients with serious infections. Eczema treatment within 2 weeks of the trials was not allowed. We looked at whether traits of children aged 2­17 years affected how well crisaborole improved eczema. We studied boys and girls by age and how bad their eczema was at the start of the study. We combined data from both clinical trials to calculate the percentages of children with clear or almost clear skin at day 29. We also studied the frequency of side effects at day 29. After 4 weeks, 33% of children receiving crisaborole compared with 22% of children receiving plain ointment had clear or almost clear skin, a meaningful difference in favor of crisaborole. This was also true across groups. Most patients did not have side effects related to crisaborole. The most common side effect related to crisaborole was application site pain. This side effect occurred in up to one in ten children receiving crisaborole. Up to 1 in 50 patients receiving plain ointment had application site pain. Few children stopped crisaborole treatment, and there were no new safety concerns. In conclusion, compared with plain ointment, crisaborole improved eczema in more children, and side effects were minor.

Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure.

OBJECTIVES: To analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases. METHODS: The analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest. RESULTS: 13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the 'infections and infestations' System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts. CONCLUSIONS: The tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.

Predictors of Systemic Exposure to Topical Crisaborole: A Nonlinear Regression Analysis.

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double-blind, vehicle-controlled phase 3 studies showed that twice-daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady-state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss ] and maximum concentration [Cmax,ss ]). PK data were available from 244 participants across 6 clinical studies (AUCss , N = 239; Cmax,ss , N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5-fold higher AUCss and Cmax,ss values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUCss and Cmax,ss . Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUCss and Cmax,ss for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2-17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.

Evaluating the Efficacy of Crisaborole Using the Atopic Dermatitis Severity Index and Percentage of Affected Body Surface Area.

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis pools results from 2 phase 3 studies (ClinicalTrials.gov, NCT02118766 [AD-301]; NCT02118792 [AD-302]) to evaluate crisaborole efficacy in patients ≥ 2 years with mild-to-moderate atopic dermatitis (per Investigator's Static Global Assessment) using the Atopic Dermatitis Severity Index (ADSI) and percentage of treatable body surface area (%BSA). Patients were randomly assigned 2:1 to receive crisaborole (n = 1,016) or vehicle (n = 506) twice daily for 28 days. ADSI scores were the sum of pruritus, erythema, exudation, excoriation, and lichenification severity scores, each graded on a 4-point scale from none (0) to severe (3). Respective mean changes in ADSI score and %BSA at day 29 were (crisaborole vs. vehicle) -3.52 versus -2.42 (p < 0.0001) and -7.43 versus -4.44 (p < 0.0001). Crisaborole was effective in treating mild-to-moderate atopic dermatitis based on ADSI and %BSA.

Efficacy and Safety of Crisaborole Ointment, 2%, for the Treatment of Mild-to-Moderate Atopic Dermatitis Across Racial and Ethnic Groups.

BACKGROUND: Atopic dermatitis is highly prevalent in black/African American, Asian, and Hispanic patients, making assessment of these populations in clinical trials important. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. In two pivotal phase III clinical trials in patients aged ≥ 2 years, crisaborole was superior to vehicle in reducing global disease severity. The most common treatment-related adverse event was application site pain. OBJECTIVE: The objective of this study was to investigate the efficacy and safety of crisaborole according to patient race and ethnicity. METHODS: A pooled post hoc analysis by race and ethnicity of the two pivotal trials and a safety extension trial was performed. Race included white or nonwhite (encompassing Asian/native Hawaiian/other Pacific Islander, black/African American, and other/American Indian/Alaskan native); ethnicity included Hispanic/Latino or not Hispanic/Latino. RESULTS: In white, nonwhite, Hispanic/Latino, and not Hispanic/Latino groups at day 29, more crisaborole- than vehicle-treated patients achieved improvements in global disease severity [Investigator's Static Global Assessment of clear/almost clear with a ≥ 2-grade improvement (white: 33.5% vs. 22.3%, nominal p < 0.001; nonwhite: 30.0% vs. 21.3%, nominal p < 0.05; Hispanic/Latino: 35.4% vs. 18.2%, nominal p < 0.01; not Hispanic/Latino: 31.3% vs. 22.8%, nominal p < 0.01)]. Crisaborole treatment also improved atopic dermatitis signs/symptoms and quality of life. Frequency of crisaborole-related adverse events was 7.1-8.5% in the pivotal trials. CONCLUSION: Across races and ethnicities, crisaborole demonstrated efficacy for the treatment of mild-to-moderate atopic dermatitis, with a low frequency of treatment-related adverse events.

Direct and Indirect Effects of Crisaborole Ointment on Quality of Life in Patients with Atopic Dermatitis: A Mediation Analysis.

Crisaborole ointment is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Using pooled data from two phase 3 studies (NCT02118766/NCT02118792), mediation modeling determined the interrelationship among pruritus, quality of life (QoL), and treatment. Patients aged ≥ 2 years received crisaborole ointment 2% or vehicle twice daily for 28 days. QoL measures were Dermatology Life Quality Index (DLQI) (≥ 16 years) and Children's Dermatology Life Quality Index (CDLQI) (2-15 years). Pruritus was assessed by the Severity of Pruritus Scale (4-point scale from 0 to 3). The indirect effect of crisaborole on QoL mediated through its effect on pruritus was 51% (DLQI model, p < 0.05) and 72% (CDLQI model, p < 0.05). Direct effect (other effects) on QoL was 49% (DLQI model, p < 0.05) and 28% (CDLQI model, p > 0.05). Mediation modeling shows that crisaborole affects QoL mostly indirectly through pruritus severity reduction.

T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13) and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during tofacitinib treatment.

BACKGROUND: Psoriasis is often treated with immunomodulatory therapies that can affect the immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor. OBJECTIVE: To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily on T-cell function in psoriasis patients. METHODS: Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg twice daily were vaccinated with T-cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13]). Patients were assessed at baseline (before vaccination) and then again 4 weeks after vaccination. For PCV-13, we evaluated serotype-specific, opsonophagocytic antibody responses, and for tetanus toxoid, we evaluated humoral responses. RESULTS: Among 60 patients who completed the study, the geometric mean fold rise from baseline for the 13 PCV serotypes at 4 weeks postvaccination varied from 8.3 (serotype 3) to 101.9 (serotype 6A). Similar results were observed for patients with and without lymphopenia at baseline. For tetanus toxoid, 51 (88%) patients had ≥2-fold and 35 (60%) patients had ≥4-fold rise in antibody concentration. LIMITATIONS: There was no placebo control. CONCLUSION: Most psoriasis patients who receive tofacitinib can mount satisfactory T-cell-dependent responses to PCV-13 and tetanus vaccines.

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.

Initiation, Switching, and Cessation of Psoriasis Treatments Among Patients with Moderate to Severe Psoriasis in the United States.

BACKGROUND: Psoriasis patients frequently switch among multiple therapies while managing their psoriasis. Determining treatment transitions is fundamental to understanding how patients access and use treatments. OBJECTIVE: We aimed to identify patterns of treatment transitions of US patients with moderate to severe psoriasis over 5 years. METHODS: This was a retrospective, longitudinal cohort study in which US patients aged ≥18 years who had at least one psoriasis claim (International Classification of Diseases, Ninth Revision [ICD-9] diagnosis) were continuously enrolled in a health plan between October 2007 and September 2012. Data from eligible patients were projected to reflect the total US insured population with moderate to severe psoriasis, and the proportions of patients who started, stopped, switched, and restarted treatment at any time between September 2011 and September 2012 were analyzed. Treatment categories were biologics, traditional oral systemics, topicals, phototherapy, lapsed from treatment, and treatment-naive. RESULTS: There were 8.9 million patients in the claims database, of whom 0.9 million (10.4%) had a psoriasis diagnosis and 46,369 (0.5%) met the inclusion criteria. When projected, 1.7 million insured patients had moderate to severe psoriasis. Of these, an estimated 807,000 patients had lapsed treatment, an additional 346,000 were receiving treatment, and 547,000 were defined as being treatment-naive. A total of 81,000 of 346,000 patients had switched treatment in the preceding year. In addition, many patients stopped (438,000) and restarted (384,000) treatment in the 12-month period. CONCLUSION: Based on health claims data, undertreatment of moderate to severe psoriasis appeared to be common.

Early clinical response to tofacitinib treatment as a predictor of subsequent efficacy: Results from two phase 3 studies of patients with moderate-to-severe plaque psoriasis.

BACKGROUND: The ability to predict response to psoriasis treatments has important implications. Tofacitinib is an oral JAK inhibitor being investigated for psoriasis. OBJECTIVE: The objective of this study is to identify and validate the clinical predictors of responses in psoriasis patients treated with tofacitinib. METHODS: Selected baseline characteristics or early improvement in Psoriasis Area and Severity Index (PASI) in the phase 3 tofacitinib study OPT 1 (NCT01276639) were evaluated as predictors for a clinical response (75% improvement in PASI [PASI75]) at week 16. Predictive ability was assessed by the area-under-the-receiver operating characteristic curve (AUC-ROC). The predictive ability of the identified variables was validated with study OPT 2 (NCT01309737). RESULTS: PASI improvement at weeks 8 and 12 demonstrated good discriminatory abilities to predict PASI75 response at week 16 (AUC-ROC ≥86% and 94%, respectively) in OPT 1. Validation with PASI50 response at week 8 in OPT 2 to predict PASI75 response at week 16 showed that the sensitivity, specificity, PPV, and NPV were 88%, 69%, 80%, and 81%, respectively, in tofacitinib-treated subjects. CONCLUSION: Achieving a PASI50 response after 8 weeks of treatment with tofacitinib in psoriasis patients appears to be a reliable predictor of achieving a PASI75 response at week 16. TRIAL REGISTRATION: clinicaltrials.gov: NCT01276639 and NCT01309737.

Under-Treatment of Patients with Moderate to Severe Psoriasis in the United States: Analysis of Medication Usage with Health Plan Data.

INTRODUCTION: Psoriasis is a chronic inflammatory disorder with significant morbidity and mortality, but a persistent gap appears to exist for the adequate treatment of patients with moderate to severe disease. As the extent of under-treatment is unknown, we attempted to determine overall treatment patterns and estimate under-treatment using a large database. METHODS: Data from the US National Health and Wellness Survey was used to estimate the proportion of patients with mild, moderate or severe psoriasis. The proportion with moderate to severe disease was estimated by excluding those with mild disease, and projecting this to the total insured US population, weighted by age and gender. Using US health plan claims data, patient totals by treatment type were determined between October 1, 2007 and September 30, 2012. Patients had to be continuously enrolled in a health plan and be ≥18 years at the end of the analysis window. Psoriasis was confirmed if patients had at least one claim of any type of psoriasis except psoriatic arthropathy (ICD-9 code 696.1). A monthly treatment history, classified by biologic, traditional oral systemic, phototherapy and topical therapy, was recorded for each patient. RESULTS: There were an estimated 1.7 million insured US patients with moderate to severe psoriasis. Of these, 1 million (59%) were not treated for their condition in the preceding year. Among 695,488 patients who were treated for psoriasis in the preceding year, 346,201 were currently receiving treatment and 349,287 had lapsed treatment. Of the patients lapsed and currently treated in this period, the numbers who received each treatment type were 156,409 (biologic), 222,657 (traditional oral systemic), 22,911 (phototherapy), and 293,511 (topical). A limitation of the study was that only insurance claims were analyzed. CONCLUSION: Moderate to severe psoriasis remains persistently untreated or under-treated. We suggest that potential barriers preventing access to care be explored. FUNDING: This study was sponsored by Pfizer Inc.

CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis.

CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an indicator of tumor prognosis. This current meta-analysis systematically reevaluated the predictive potential of CD147/EMMPRIN in various cancers. We searched PubMed and Embase databases to screen the literature. Fixed-effect and random-effect meta-analytical techniques were used to correlate CD147 expression with outcome measures. A total of 53 studies that included 68 datasets were eligible for inclusion in the final analysis. We found a significant association between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. In addition, CD147/EMMPRIN overexpression predicted a high risk for chemotherapy drugs resistance. CD147/EMMPRIN is a central player in tumor progression and predicts a poor prognosis, including in patients who have received chemo-radiotherapy. Our results provide the evidence that CD147/EMMPRIN could be a potential therapeutic target for cancers.

Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory condition that is associated with a higher risk of cardiovascular (CV) disease. Tofacitinib is being investigated as a treatment for psoriasis. OBJECTIVE: We sought to evaluate the effects of tofacitinib on CV risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis. METHODS: Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib. RESULTS: Tofacitinib treatment was associated with small, dose-dependent increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged. There were no changes in blood pressure and glycated hemoglobin levels; C-reactive protein levels decreased. The IRs of a MACE were low and similar for both tofacitinib doses. Among 3623 subjects treated with tofacitinib, the total patient-years of exposure was 5204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95% confidence interval, 0.22-0.57) patients with events per 100 patient-years. LIMITATIONS: There was relatively short follow-up time for patients who had MACEs. CONCLUSIONS: While treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several CV risk factors, and the incidence of MACEs is low.

Efficacy of Tofacitinib for the Treatment of Moderate-to-Severe Chronic Plaque Psoriasis in Patient Subgroups from Two Randomised Phase 3 Trials.

BACKGROUND: Tofacitinib is a Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. We report efficacy of tofacitinib in patient subgroups based on pooled data from two Phase 3 trials (NCT01276639, NCT01309737).
OBJECTIVES: To assess consistency of treatment effects of tofacitinib versus placebo in subgroups defined by baseline characteristics, and to ascertain whether baseline characteristics are of value in optimizing tofacitinib use.
METHODS: Pooled data from the two trials were used to evaluate ≥75% reduction in PASI from baseline (PASI75 response) in subgroups defined by age, age at psoriasis onset, gender, race, geographical region, weight, body mass index, diabetes, metabolic syndrome, tobacco/alcohol use, psoriatic arthritis, disease activity, and prior therapy.
RESULTS: Week 16 PASI75 response rates (N=1843) were 43%, 59% and 9% with tofacitinib 5 and 10mg twice daily (BID) and placebo, respectively (each P<0.0001 versus placebo). Tofacitinib 5 and 10mg BID were effective regardless of baseline characteristics. Across subgroups, tofacitinib generally produced greater response rates with the 10 versus 5mg BID dosage. Lower absolute response rates were seen in heavier patients and patients with prior biologic experience.
CONCLUSIONS: Both tofacitinib dosages demonstrated consistent efficacy versus placebo across subgroups. Lower response rates were seen in heavier patients and those with prior biologic experience. Tofacitinib 10mg BID resulted in a substantial proportion of responders regardless of baseline characteristics.

J Drugs Dermatol. 2016;15(5):568-580.

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, 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.

Randomized Pilot Clinical Trial of Tofacitinib Solution for Plaque Psoriasis: Challenges of the Intra-Subject Study Design.

Intra-subject, left-right, randomized, controlled study designs are often used for proof-of-concept studies in dermatology. This design was used to evaluate the safety and efficacy of a topical solution of tofacitinib (NCT00678561), a small-molecule Janus kinase inhibitor under investigation for the topical and oral treatment of patients with chronic plaque psoriasis. Eighty-one patients, each with matched left and right target plaques, were randomized to 2%, 0.2%, or 0.02% tofacitinib or vehicle solution once or twice daily. Patients treated one plaque as per their randomization group (2%, 0.2%, 0.02% tofacitinib, or vehicle solution), and used vehicle to treat the contralateral plaque for 4 weeks. Except during clinic visits, study drug applications were performed unsupervised outside the clinical trial site. Intra-subject, vehicle-adjusted mean percent change from baseline in Target Plaque Severity Score at week 4 (primary efficacy endpoint) was not significantly different from baseline for any treatment group (P values of 0.28-0.68). However, skin biopsy analyses detected tofacitinib in both tofacitinib- and vehicle-treated plaques of some patients, suggesting cross-contamination or solution misapplication. Lack of efficacy with tofacitinib relative to vehicle may be due to the intra-subject study design with unsupervised applications. These findings have potential implications for future intra-subject studies of topical treatments.

Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.

BACKGROUND: New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population. METHODS: In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591. FINDINGS: Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events. INTERPRETATION: In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis. FUNDING: Pfizer Inc.

Effects of tofacitinib on lymphocyte sub-populations, CMV and EBV viral load in patients with plaque psoriasis.

BACKGROUND: Plaque psoriasis is a debilitating skin condition that affects approximately 2% of the adult population and for which there is currently no cure. Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. METHODS: The design of this study has been reported previously (NCT00678210). Patients with moderate to severe chronic plaque psoriasis received tofacitinib (2 mg, 5 mg, or 15 mg) or placebo, twice daily, for 12 weeks. Lymphocyte sub-populations, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA were measured at baseline and up to Week 12. RESULTS: Tofacitinib was associated with modest, dose-dependent percentage increases from baseline in median B cell count at Week 4 (24-68%) and Week 12 (18-43%) and percentage reductions from baseline in median natural killer cell count at Week 4 (11-40%). The proportion of patients with detectable CMV and EBV DNA (defined as >0 copies/500 ng total DNA) increased post-baseline in tofacitinib-treated patients. However, multivariate analyses found no relationship between changes in CMV or EBV viral load and changes in lymphocyte sub-populations or tofacitinib treatment. CONCLUSIONS: Twelve weeks of treatment with tofacitinib had no clinically significant effects on CMV or EBV viral load, suggesting that lymphocyte sub-populations critical to the response to chronic viral infections and viral reactivation were not significantly affected. Replication of these findings during long-term use of tofacitinib will allow confirmation of this observation.