Anna M. Tallman

Efficacy of tofacitinib for the treatment of nail psoriasis: Two 52-week, randomized, controlled phase 3 studies in patients with moderate-to-severe plaque psoriasis

Background Tofacitinib is an oral Janus kinase inhibitor. Efficacy and safety of tofacitinib in patients with moderate‐to‐severe plaque psoriasis have been demonstrated. Objective We sought to assess the efficacy of tofacitinib for the treatment of nail psoriasis over a period of 52 weeks. Methods In 2 identical phase 3 studies (OPT Pivotal 1 and 2), patients were randomized 2:2:1 to receive tofacitinib 5 mg, tofacitinib 10 mg, or placebo, twice daily. At week 16, placebo‐treated patients were re‐randomized to tofacitinib. This post hoc analysis of patients with existing nail psoriasis assessed the Nail Psoriasis Severity Index (NAPSI) score and proportions of patients achieving ≥50% reduction in NAPSI from baseline (NAPSI50), NAPSI75, or NAPSI100. Results Baseline mean NAPSI scores for patients treated with tofacitinib 5 mg (N = 487), tofacitinib 10 mg (N = 476), and placebo (N = 233) twice daily were 27.0, 27.3, and 26.9, respectively. At week 16, significantly (all P < .05) more patients receiving tofacitinib 5 mg and tofacitinib 10 mg versus placebo twice daily achieved NAPSI50 (32.8%, 44.2% vs 12.0%), NAPSI75 (16.9%, 28.1% vs 6.8%), and NAPSI100 (10.3%, 18.2% vs 5.1%), respectively. Improvements were sustained to week 52. Limitations Limitations include discontinuation of clinical nonresponders at week 28. Conclusions Tofacitinib treatment resulted in improvements in nail psoriasis versus placebo at week 16; improvements were maintained over 52 weeks [NCT01276639; NCT01309737]. Abbreviations used: BID: twice daily; BSA: body surface area; FAS: full analysis set; HRQoL: health‐related quality of life; JAK: Janus kinase; LS: least squares; NAPSI: Nail Psoriasis Severity Index; NAPSI50: 50% reduction from baseline in NAPSI score; NAPSI75: 75% reduction from baseline in NAPSI score; NAPSI100: 100% reduction from baseline in NAPSI score; NRI: nonresponder imputation; PASI: Psoriasis Area and Severity Index; PASI75: 75% reduction from baseline in PASI score; PGA: Physicians Global Assessment; PsA: psoriatic arthritis; Q: quartile; SD: standard deviation; SE: standard error.

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

Abstract 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

Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study

Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open‐label extension study of tofacitinib in psoriasis are reported.

Tofacitinib for the treatment of moderate to severe chronic plaque psoriasis in Japanese patients: Subgroup analyses from a randomized, placebo‐controlled phase 3 trial

Tofacitinib is an oral Janus kinase inhibitor. These post‐hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52‐week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo‐treated patients advanced to tofacitinib at week 16. Primary efficacy end‐points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index (PASI‐75) and Physicians Global Assessment (PGA) of “clear” or “almost clear” (PGA response) at week 16. Other end‐points included: Itch Severity Item (ISI), Dermatology Life Quality Index (DLQI) score and Nail Psoriasis Severity Index (NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI‐75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis.

Quantitative Evaluations of Time‐Course and Treatment Effects of Systemic Agents for Psoriasis: A Model‐Based Meta‐Analysis

Aggregate data model‐based meta‐analysis is a regression approach to compare the dose–response and/or time‐course across different treatments using summary level data from the literature. Literature search and systematic review following the Cochrane approach yielded 912 sources for investigational and approved treatments for psoriasis. In addition, data for tofacitinib were obtained from an internal database. Tofacitinib is an oral Janus kinase inhibitor. Two mathematical models were developed for Psoriasis Area and Severity Index (PASI) response in moderate to severe psoriasis patients to quantify the time to maximum effect for PASI75 and to evaluate the dose–response relationship for PASI responders (PASI50, PASI75, PASI90, PASI100) at Week 12. Body weight exhibited an inverse effect on the placebo component of both models, suggesting that body weight affects the overall PASI response regardless of drug. This analysis provides a quantitative framework for efficacy comparisons across psoriasis treatments.

Pharmacokinetic Characteristics of Tofacitinib in Adult Patients With Moderate to Severe Chronic Plaque Psoriasis

Tofacitinib is an oral Janus kinase (JAK) inhibitor. This study characterized the pharmacokinetics of tofacitinib in patients with psoriasis and evaluated the impact of patient factors on disposition. Pooled phase 2/3 data (2981 patients: 9735 concentrations, dose range: 2‐15 mg twice daily) up to 56 weeks were used for modeling. A one‐compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution, zero‐order absorption (duration, D), with interindividual variability and inter‐occasion variability terms, described tofacitinib pharmacokinetics. A full covariate model incorporated effects for age, sex, race, ethnicity, and baseline variables (body weight, Psoriasis Area Severity Index [PASI], C‐reactive protein [CRP], creatinine clearance [CrCl]). The parameter estimates (95%CI) for CL/F, Vd/F, and D in a typical individual (white, male, 86 kg, 46 years, CrCl 121 mL/min, PASI 19.8, and CRP 0.267 mg/dL) were 26.7 (25.9, 27.5) L/h, 125 (120.8, 128.3) liters, and 0.69 (0.646, 0.735) hours, respectively. Only CrCl led to clinically relevant changes in exposure. The analysis suggested no dosing modifications for age, body weight, sex, race, ethnicity, baseline PASI, or CRP based on the magnitude of exposure change. Dosing adjustments for renal impairment were derived from a separate phase 1 study.

Assessment of pruritus in atopic dermatitis: validation of the Severity of Pruritus Scale (SPS)

Introduction: Pruritus, or itch, is a central feature of atopic dermatitis (AD) and is often cited as the most bothersome symptom. The Severity of Pruritus Scale (SPS) is a 4-point rating scale adapted from the Atopic Dermatitis Severity Index to provide a measure of pruritus severity within a 24-hour recall period. The objective of this analysis was to assess the qualitative and quantitative validity of the SPS in AD. Methods: Content validity of the SPS was evaluated qualitatively in US patients with AD. Psychometric properties of the SPS were evaluated using data from 2 phase 3 trials conducted to investigate crisaborole in mild to moderate AD (study AD-301: NCT02118766; study AD-302: NCT02118792). Results: Fourteen patients were included in the qualitative analysis, considered adequate because of the single-item, single-concept nature of the SPS. Itch was the most prevalent symptom, and the SPS was easily understood and completed in US English (n=9) and US Spanish (n=5). The psychometric analysis used data from 1344 patients. Test-retest reliability analysis identified an intraclass correlation coefficient of 0.54 for a single SPS observation, and at least 0.70 when at least 2 SPS observations were averaged. SPS scores correlated with Investigator’s Static Global Assessment (ISGA) scores, measures of quality of life, and 4 of 5 signs of AD (Pearson correlations, ≥0.40 at day 29). The difference in score between the no disease group/clear (ISGA 0) and the severe disease group (ISGA 4) was 0.80. The clinically important difference was estimated to be 0.20 and the clinically important response was estimated to be at least a 0.19-point reduction from baseline. Discussion: The SPS is an appropriate tool to assess itch in patients with AD and is a valid and reliable measure of pruritus severity.

Effect of crisaborole topical ointment, 2%, on atopic dermatitis–associated pruritus: an extended analysis of 2 phase 3 clinical trials

Introduction: Pruritus is an essential feature of atopic dermatitis (AD) and is widely considered the most distressing symptom. Crisaborole ointment is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate AD. The efficacy of crisaborole for AD-associated pruritus was assessed in 2 phase 3 trials using the Severity of Pruritus Scale (SPS). Post hoc validation of the SPS identified that 1 SPS observation provided inadequate test-retest reliability. Therefore, extended analyses were conducted using at least 2 SPS observations for robust assessment of pruritus in the phase 3 crisaborole trials. Methods: Data were analyzed from 2 identically designed, vehicle-controlled, double-blind, phase 3 trials designed to investigate the efficacy and safety of crisaborole in AD patients aged 2 years and above (AD-301: NCT02118766; AD-302: NCT02118792). At least 2 SPS observations were averaged for acceptable test-retest reliability. Results: At least 2 baseline observations were available for 569 patients in AD-301 and 561 patients in AD-302. Median time to pruritus improvement (SPS score ⩽1 with at least 1-point improvement from baseline) was shorter with crisaborole than with vehicle (AD-301: 5.0 vs. 10.0 d, P=0.0003; AD-302: 6.0 vs. 9.0 d, P=0.0087). At week 4, more crisaborole-treated patients than vehicle-treated patients experienced pruritus improvement (AD-301: 37% vs. 21%, P<0.0001; AD-302: 34% vs. 21%, P=0.0006), mean pruritus scores were lower with crisaborole than with vehicle (AD-301: 0.97 vs. 1.28, P<0.0001; AD-302: 1.08 vs. 1.35, P<0.0001), and more crisaborole-treated patients than vehicle-treated patients experienced a clinically important pruritus response (AD-301: 75% vs. 57%, P<0.0001; AD-302: 72% vs. 64%, P=0.0828). Conclusions: These extended analyses show that patients treated with crisaborole experienced rapid and clinically relevant improvement in AD-associated pruritus.

The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long‐term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD.

Patient impact and economic burden of mild-to-moderate atopic dermatitis

Abstract Objective: To present a systematic review of studies conducted to evaluate patient impact and economic burden of mild-to-moderate atopic dermatitis. Methods: A MEDLINE (via PubMed), Excerpta Medica database (Embase), and Cochrane Library search for English-language articles published January 1, 1996–December 31, 2016 was performed. Abstracts were manually reviewed from 2015–2016 from 10 leading conferences and congresses associated with atopic dermatitis. Manuscripts were reviewed for inclusion in two main categories within the review: patient impact of mild-to-moderate atopic dermatitis and economic burden of atopic dermatitis. Excluded from this dataset were any patients in these studies who had severe atopic dermatitis, moderate-to-severe atopic dermatitis, or atopic dermatitis of unspecified severity. Results: In total, 222 studies qualified for inclusion in the analysis; this report focuses on the 76 studies that reported results stratified by disease severity. Measured by general and specific instruments, even mild-to-moderate atopic dermatitis reduces the overall quality-of-life of patients and their caregivers/families. Disease severity assessed by validated severity instruments directly correlated with quality-of-life. Treatment of atopic dermatitis can improve the quality-of-life of patients and their caregivers/families by alleviation of symptoms and reduction in severity. In general, total costs increased as disease severity increased; even mild atopic dermatitis imposed substantial costs. Conclusions: The results emphasize the impact of atopic dermatitis, especially mild atopic dermatitis, on patient lives and finances, including education of clinicians, payers, and patients regarding benefits associated with treatment adherence.