Efficacy and safety of ritlecitinib in adolescents with alopecia areata: Results from the ALLEGRO phase 2b/3 randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: This subgroup analysis of the ALLEGRO phase 2b/3 trial (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, for the treatment of alopecia areata (AA) in patients aged 12-17 years. METHODS: In ALLEGRO-2b/3, patients aged ≥12 years with AA and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (±4-week 200-mg loading dose) or 10 mg or placebo for 24 weeks. In a subsequent 24-week extension period, ritlecitinib groups continued their doses, and patients initially assigned to placebo switched to 200/50 or 50 mg daily. Clinician- and patient-reported hair regrowth outcomes and safety were assessed. RESULTS: In total, 105 adolescents were randomized. At Week 24, 17%-28% of adolescents achieved a Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp without hair) in the ritlecitinib 30 mg and higher treatment groups versus 0% for placebo. At Week 48, 25%-50% of patients had a SALT score ≤20 across ritlecitinib treatment groups (30 mg and higher). Adolescents reporting that their AA "moderately" or "greatly" improved were 45%-61% in the ritlecitinib groups (30 mg and higher) (vs. 10%-22% for placebo) at Week 24 and 44%-80% at Week 48. The most common adverse events in adolescents were headache, acne, and nasopharyngitis. No deaths, major adverse cardiovascular events, malignancies, pulmonary embolisms, opportunistic infections, or herpes zoster infections were reported. CONCLUSION: Ritlecitinib treatment demonstrated clinician-reported efficacy, patient-reported improvement, and an acceptable safety profile through Week 48 in adolescents with AA with ≥50% scalp hair loss.

Overview of alopecia areata for managed care and payer stakeholders in the United States.

Alopecia areata (AA) is an autoimmune disease with a complex pathophysiology resulting in nonscarring hair loss in genetically susceptible individuals. We aim to provide health care decision makers an overview of the pathophysiology of AA, its causes and diagnosis, disease burden, costs, comorbidities, and information on current and emerging treatment options to help inform payer benefit design and prior authorization decisions. Literature searches for AA were conducted using PubMed between 2016 and 2022 inclusive, using search terms covering the causes and diagnosis of AA, pathophysiology, comorbidities, disease management, costs, and impact on quality of life (QoL). AA is a polygenic autoimmune disease that significantly impacts QoL. Patients with AA face economic burden and an increased prevalence of psychiatric disease, as well as numerous systemic comorbidities. AA is predominantly treated using corticosteroids, systemic immunosuppressants, and topical immunotherapy. Currently, there are limited data to reliably inform effective treatment decisions, particularly for patients with extensive disease. However, several novel therapies that specifically target the immunopathology of AA have emerged, including Janus kinase (JAK) 1/2 inhibitors such as baricitinib and deuruxolitinib, and the JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinase inhibitor ritlecitinib. To support disease management, a disease severity classification tool, the Alopecia Areata Severity Scale, was recently developed that evaluates patients with AA holistically (extent of hair loss and other factors). AA is an autoimmune disease often associated with comorbidities and poor QoL, which poses a significant economic burden for payers and patients. Better treatments are needed for patients, and JAK inhibitors, among other approaches, may address this tremendous unmet medical need. DISCLOSURES: Dr King reports seats on advisory boards for and/or is a consultant and/or clinical trial investigator for AbbVie, Aclaris Therapeutics Inc, AltruBio Inc, Almirall, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences Inc, Eli Lilly and Company, Equillium, Incyte Corp, Janssen Pharmaceuticals, LEO Pharma, Otsuka/Visterra Inc, Pfizer, Regeneron, Sanofi Genzyme, TWi Biotechnology Inc, and Viela Bio; and speakers bureaus for AbbVie, Incyte, LEO Pharma, Pfizer, Regeneron, and Sanofi Genzyme. Pezalla is a paid consultant to Pfizer for market access and payer strategy concerns; Fung, Tran, Bourret, Takiya, Peeples-Lamirande, and Napatalung are employees of Pfizer and hold stock in Pfizer. This article was funded by Pfizer.

Impact of Crisaborole on Sleep Outcomes in Pediatric Patients with Mild-to-Moderate Atopic Dermatitis.

INTRODUCTION: Using data from three clinical trials, the effect of crisaborole treatment on sleep outcomes for pediatric patients with atopic dermatitis (AD) and their families was examined. METHODS: This analysis comprised patients aged 2 to < 16 years from the double-blind phase 3 CrisADe CORE 1 (NCT02118766) and CORE 2 (NCT02118792) studies, families of patients aged 2 to < 18 years from CORE 1 and CORE 2, and patients aged 3 months to < 2 years from the open-label phase 4 CrisADe CARE 1 study (NCT03356977), all with mild-to-moderate AD who received crisaborole ointment 2% twice daily for 28 days. Sleep outcomes were assessed via the Children's Dermatology Life Quality Index and Dermatitis Family Impact questionnaires in CORE 1 and CORE 2 and the Patient-Oriented Eczema Measure questionnaire in CARE 1. RESULTS: In CORE 1 and CORE 2, a significantly lower proportion of crisaborole-treated patients than vehicle-treated patients reported sleep disruption at day 29 (48.5% versus 57.7%, p = 0.001). The proportion of families whose sleep was affected by their child's AD in the preceding week was also significantly lower in the crisaborole group (35.8% versus 43.1%, p = 0.02) at day 29. At day 29 in CARE 1, the proportion of crisaborole-treated patients who experienced ≥ 1 night of disturbed sleep in the previous week decreased by 32.1% from baseline. CONCLUSION: These results suggest that crisaborole improves sleep outcomes in pediatric patients with mild-to-moderate AD and their families.

Atopic dermatitis (AD), also known as eczema, is a chronic skin disease that causes red or flaky skin patches that can become infected and itch. Children with AD often experience sleep disturbance, including difficulty falling asleep, restless sleep, waking up more frequently, and daytime drowsiness. Problems with sleep quality negatively impact children with AD, as well as their caregivers. Crisaborole ointment is applied to the skin and has been shown to improve the symptoms of AD in children and adults. This study examined how treatment with crisaborole affected sleep quality for children and their caregivers in three clinical trials. Children in these studies took crisaborole for 28 days. Researchers found that crisaborole treatment improved sleep in children with mild-to-moderate AD and their caregivers. This was determined using four measures. First, a smaller proportion of children who were treated with crisaborole experienced sleep disruption compared with those to whom a vehicle was applied (an ointment with no drug). Second, a smaller proportion of caregivers of children with AD who were treated with crisaborole reported effects on their sleep, compared with children to whom a vehicle was applied. Third, a smaller proportion of children with AD who were treated with crisaborole, as well as their caregivers, had ≥ 1 night per week of disturbed sleep after treatment compared with before treatment. Fourth, the caregivers of children treated with crisaborole reported significantly less exhaustion and tiredness because of the child's AD. These results suggest that treatment with crisaborole improves sleep outcomes in children with mild-to-moderate AD and their caregivers.

Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: an analysis of pooled data from phase 3 studies.

OBJECTIVE: Tofacitinib is an oral Janus kinase for the treatment of rheumatoid arthritis (RA). This post hoc analysis assessed whether baseline body mass index (BMI) impacts tofacitinib efficacy in patients with RA. METHODS: Pooled data from six phase 3 studies in patients receiving tofacitinib 5 mg (N=1589) or 10 mg (N=1611) twice daily or placebo (advancing to active treatment at months 3 or 6; N=680), ±conventional synthetic disease-modifying antirheumatic drugs, were stratified by baseline BMI (<25, 25 to <30, ≥30 kg/m2). Endpoints (through to month 6) were assessed descriptively: American College of Rheumatology 20/50/70 response rates; changes from baseline (∆) in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), DAS28-4(C-reactive protein), Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain; and proportions of patients achieving DAS28-4(ESR) ≥1.2 and HAQ-DI ≥0.22 decreases from baseline, low disease activity (DAS28-4(ESR) ≤3.2 or CDAI ≤10) and radiographic non-progression (Δmodified Total Sharp Score ≤0.5; months 12 and 24). Estimates were adjusted using multivariable models for selected outcomes. Univariate/multivariable regression analyses determined predictors of month 6 outcomes. RESULTS: Of 3880 patients included, 1690 (43.6%), 1173 (30.2%) and 1017 (26.2%) had baseline BMI <25, 25 to <30 and ≥30 kg/m2, respectively. Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) were generally not clinically meaningful across BMI categories within treatment groups. In regression analyses, BMI was not consistently associated with selected outcomes. CONCLUSIONS: Baseline BMI did not consistently affect tofacitinib response suggesting that tofacitinib is an effective oral treatment option for adults with moderate to severe RA regardless of baseline BMI, including patients with BMI ≥30 kg/m2. TRIAL REGISTRATION NUMBERS: NCT00814307, NCT01039688; NCT00960440; NCT00847613; NCT00856544; NCT00853385.

Efficacy and safety of tofacitinib by background methotrexate dose in psoriatic arthritis: post hoc exploratory analysis from two phase III trials.

OBJECTIVE: Analyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA). METHODS: This post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician's global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient's global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters. RESULTS: Five hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week. CONCLUSION: Efficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week. TRIAL REGISTRATION: ClinicalTrials.gov . Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points • Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis. • This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis. • Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily. • Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.

Patient and caregiver preferences on treatment attributes for atopic dermatitis.

BACKGROUND: The expanding number of potential treatment options for atopic dermatitis (AD) highlights the need to better understand the treatment preferences of individuals with AD. OBJECTIVE: This study identified attributes that most greatly influenced treatment preferences of adults/adolescents/caregivers of children with mild/moderate/severe AD. METHODS: Adults (≥18 years), adolescents (12-17 years), and caregivers of children (2-11 years) with mild, moderate, or severe AD in the United States (US) and United Kingdom (UK) participated in semistructured interviews. Thematic analysis was used to identify and generate themes across the interview results describing the treatment attributes of greatest importance to participants. RESULTS: Qualitative interviews were conducted with 35 adults, 35 caregivers, and 33 adolescent participants across both countries (n = 103; US = 51; UK = 52) and all severity groups (mild = 43; moderate = 47; severe = 13). The most important treatment attributes included efficacy (96.1%; speed and duration of symptom relief), mode of administration (66.0%; route of administration, frequency, and convenience), and side effects (55.3%, short-term, long-term, and general). CONCLUSIONS: Efficacy, mode of administration, and side effects were the most important attributes that influenced AD treatment preferences for patients and caregivers across different countries, ages, and disease severity. These results may assist patients/caregivers/clinicians in shared decision-making discussions to improve treatment adherence and outcomes.

Efficacy and safety of crisaborole in patients with mild-to-moderate atopic dermatitis and other atopic comorbidities.

Background: Crisaborole is a nonsteroidal anti-inflammatory phosphodiesterase 4 inhibitor that is approved for the treatment of patients with mild-to-moderate atopic dermatitis (AD); however, the efficacy and safety of crisaborole in patients with AD and other atopic comorbidities have not been investigated. Objective: This post hoc pooled analysis of the pivotal phase III studies (CrisADe CORE 1 and CORE 2) assessed the efficacy and safety of crisaborole versus vehicle in patients aged ≥ 2 years with mild-to-moderate AD and other atopic comorbidities. Methods: Patients with mild-to-moderate AD and a medical history of asthma, allergic rhinitis, or food allergies were identified. Efficacy assessments included the proportion of patients who achieved Investigator's Static Global Assessment (ISGA) success at day 29, ISGA clear or almost clear at day 29, and improvement in the Severity of Pruritus Scale score at week 4. Safety was assessed via treatment-emergent adverse events (TEAEs). Results: This analysis included 1522 patients (crisaborole, 1016; vehicle, 506); 26.2, 15.9, and 16.5% had a medical history of asthma, allergic rhinitis, and food allergies, respectively. The mean age was 12.2 years. A significantly greater proportion of patients treated with crisaborole achieved ISGA success at day 29 compared with patients treated with vehicle for most subgroups analyzed. Furthermore, a significantly greater proportion of patients treated with crisaborole achieved ISGA clear or almost clear at day 29 across all subgroups and demonstrated improvement in the Severity of Pruritus Scale score at week 4 versus patients treated with vehicle in most of the subgroups. Overall, most TEAEs were mild or moderate in severity; the most common treatment-related TEAE in patients with atopic comorbidities was application-site pain (crisaborole, 5.1%; vehicle, 1.7%). Conclusion: Crisaborole was efficacious and well tolerated in patients with mild-to-moderate AD and other atopic comorbidities, which suggested that crisaborole should be considered for the management of AD in this population. Clinical Trials NCT02118766 (CrisADe CORE 1) and NCT02118792 (CrisADe CORE 2), www.clinicaltrials.gov.

Efficacy and Safety Trends with Continuous, Long-Term Crisaborole Use in Patients Aged ≥ 2 Years with Mild-to-Moderate Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease often requiring long-term treatment. Crisaborole significantly improved global AD signs and symptoms in 28-day phase 3 studies of patients aged ≥ 2 years with mild-to-moderate AD (Investigator's Static Global Assessment [ISGA] 2 or 3). A post hoc analysis of a long-term, open-label extension study was conducted to assess efficacy and safety trends of crisaborole in patients stratified by the number of initial consecutive crisaborole treatment cycles, defined as the number of treatment cycles completed before achievement of ISGA 0 (clear)/1 (almost clear). METHODS: Patients completing phase 3 studies without drug-related safety issues that precluded further crisaborole treatment were analyzed. Patients with ISGA 0/1 at baseline (the end of a 28-day cycle) did not receive crisaborole for the next 28-day cycle (off-treatment), whereas patients with ISGA ≥ 2 received crisaborole for the next 28-day cycle (on-treatment). Patients were stratified by number of initial consecutive crisaborole treatment cycles. Efficacy was assessed by achievement and maintenance of ISGA 0/1, and safety was assessed by incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs (TRAEs). RESULTS: Overall, 418 patients were included in exclusive cohorts based on number of consecutive on-treatment cycles (1 on-treatment cycle, n = 133; 2 consecutive on-treatment cycles, n = 106; 3 consecutive on-treatment cycles, n = 106; 4 consecutive on-treatment cycles, n = 73). After one to four initial consecutive on-treatment cycles, 77.6, 76.3, 59.4, and 43.1% of patients, respectively, achieved ISGA 0/1. Of these patients, 49.5, 37.8, 44.4, and 45.2%, respectively, maintained ISGA 0/1 at the end of a 28-day cycle off-treatment. Incidence of TRAEs was 4.5, 4.7, 3.8, and 1.4% for patients receiving one to four consecutive on-treatment cycles, respectively. One patient discontinued because of AEs. CONCLUSION: These results support the efficacious and safe continuous, long-term use of crisaborole for the management of mild-to-moderate AD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02118766, NCT02118792.

Eczema is a skin disease that often requires long-term treatment. Crisaborole ointment improved mild-to-moderate eczema after 28 days of continuous use in two phase 3 clinical trials that included patients aged ≥ 2 years. In the study reported here we tested whether eczema improved with continuous crisaborole use after one to four back-to-back treatment periods, or 28­112 days. Patients who completed either of the aforementioned phase 3 clinical trials were included in this study. Patients received crisaborole for the next 28-day period if they had eczema rashes. Patients with clear or almost clear skin did not receive crisaborole for 28 days. Our study included a total of 418 patients. After one to four treatment periods, 78, 76, 59, and 43% of patients, respectively, had clear or almost clear skin. Of these patients, 50, 38, 44, and 45% still had clear or almost clear skin after stopping treatment for 28 days. Fewer than one in 20 patients had side effects related to crisaborole after one to four treatment periods. The most common side effect at the application site that was related to crisaborole was pain, particularly stinging and burning. Up to one in 50 patients had application site pain. One patient stopped taking crisaborole because of side effects. In conclusion, these results suggest that long-term crisaborole use is effective and safe.

Demographics and Baseline Disease Characteristics of Early Responders to Crisaborole for Atopic Dermatitis.

INTRODUCTION: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). This post hoc, pooled analysis identified demographic characteristics associated with early response to crisaborole. METHODS: Early response was defined as day 8 Investigator’s Static Global Assessment (ISGA) success (clear [0] or almost clear [1] with ≥2-grade improvement), ISGA clear/almost clear, or Severity of Pruritus Scale (SPS) response (≥1-point improvement). Correlations between early response and day-29 response were calculated. RESULTS: Patients were more likely to be early ISGA success responders if they were aged <12 years (P=0.0023), were white (P=0.0316), had moderate baseline disease by ISGA (P=0.0003), had not received prior AD treatment (P=0.0213), had disease duration shorter than or equal to the median (≤6.45 years; P=0.0349), or did not concurrently use antihistamines (P=0.0148). Similar early response results were observed for patients achieving ISGA clear or almost clear; however, they were more likely to have mild baseline disease by ISGA (P<0.0001) or mild percentage of treatable body surface area involvement (5 to <16; P<0.0001). Patients aged <12 years (P=0.0001) or with moderate baseline disease (P=0.0475) were more likely to be early responders based on SPS criteria. By all 3 definitions, patients who achieved early response at day 8 were more likely to be responders at day 29 (P<0.0001). CONCLUSION: Based on this analysis, patients aged <12 years were more likely to be early responders to crisaborole per all 3 definitions. Early response to crisaborole was a predictor of response at day 29. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02118766 and NCT02118792 J Drugs Dermatol. 2020;19(6): doi:10.36849/JDD.2020.5095THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1).

BACKGROUND: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). OBJECTIVES: The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study. METHODS: Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory). RESULTS: Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was - 57.5%, and mean change in Patient-Oriented Eczema Measure total score was - 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years. CONCLUSIONS: In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mild-to-moderate AD with systemic exposures similar to patients aged ≥ 2 years. CLINICAL TRIAL REGISTRATION: NCT03356977.

Atopic dermatitis (AD) is a skin disease that causes inflamed and itchy skin. Crisaborole is an ointment that is approved to treat patients aged 2 years and older with mild-to-moderate AD. This clinical trial studied crisaborole in infants with mild-to-moderate AD who were 3 to under 24 months old. These infants were treated with crisaborole twice a day for 28 days. The trial studied crisaborole's safety, effectiveness, and absorption into the bloodstream. In total, 137 infants were treated. Although side effects of some sort occurred in about two-thirds of patients, only 1 in 6 patients experienced side effects that were attributed to crisaborole. When these side effects did occur, these were mainly pain, discomfort, or redness where crisaborole was applied. Fewer than 1 in 25 patients experienced each side effect where crisaborole was applied. The doctors saw improvement in the AD symptoms of some patients at day 29 of the study compared to the beginning of the study. Crisaborole blood-level measurements in this age group were consistent with those seen in patients aged 2 years and older. Overall, crisaborole was considered well tolerated and effective in infants (3 to under 24 months old) with mild-to-moderate AD. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: An Open-Label, Phase 4 Study (MP4 40891 MB).

Re-establishment of efficacy of tofacitinib, an oral JAK inhibitor, after temporary discontinuation in patients with rheumatoid arthritis.

INTRODUCTION/OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post-hoc analysis evaluated the effect of temporary discontinuation and reinitiation of tofacitinib on disease control in patients with RA in the vaccine sub-study of the long-term extension (LTE) study ORAL Sequel (NCT00413699). METHODS: The sub-study of ORAL Sequel was a randomized, parallel-group, open-label study. Patients who received tofacitinib 10 mg twice daily for ≥ 3 months in ORAL Sequel were randomized to receive continuous (tofacitinib monotherapy/with methotrexate) or interrupted (tofacitinib withdrawn for 2 weeks post-randomization then reinitiated as monotherapy/with methotrexate) treatment. Efficacy assessments included ACR20/50/70 response rates, change from baseline (∆) in C-reactive protein (CRP), Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4 [ESR]), Clinical Disease Activity Index (CDAI), Patient Global Assessment of arthritis (PtGA), Pain (Visual Analog Scale [VAS]), and Physician Global Assessment of arthritis (PGA). Safety was assessed throughout. RESULTS: The sub-study included 99 patients each in the continuous and interrupted treatment groups. ACR20/50 response rates, ∆CRP, ∆HAQ-DI (day 15), ∆DAS28-4 (ESR), ∆CDAI, ∆PtGA, ∆Pain (VAS), and ∆PGA were significantly worse in interrupted vs continuous patients during dose interruption, but were generally similar to pre-interruption/continuous treatment levels 28 days post-reinitiation. A numerically higher proportion of interrupted patients reported adverse events (49.5%) vs continuous patients (35.4%). CONCLUSIONS: Tofacitinib efficacy can be re-established after temporary withdrawal and reinitiation. The safety profile of patients who temporarily discontinued tofacitinib in the sub-study was consistent with previous tofacitinib LTE studies over 9 years. CLINICAL TRIAL REGISTRATION NUMBER: NCT00413699 Key Points • In this sub-study of the long-term extension (LTE) study, ORAL Sequel, the efficacy of tofacitinib was re-established after temporary withdrawal (2 weeks) and reinitation of treatment in patients with RA. • Patients with RA who temporarily discontinued tofacitinib had similar safety events to those reported in previous LTE studies. • The results of this sub-study were consistent with a post-hoc analysis of pooled data from two LTE studies, ORAL Sequel and A3921041, which assessed the efficacy of tofacitinib following a treatment discontinuation period of 14-30 days.

Live Zoster Vaccine in Patients With Rheumatoid Arthritis Treated With Tofacitinib With or Without Methotrexate, or Adalimumab With Methotrexate: A Post Hoc Analysis of Data From a Phase IIIb/IV Randomized Study.

OBJECTIVE: To explore herpes zoster (HZ) rates and live zoster vaccine (LZV) safety in a subset of patients with rheumatoid arthritis who received LZV before tofacitinib ± methotrexate (MTX), or adalimumab (ADA) plus MTX in the ORAL Strategy. METHODS: ORAL Strategy was a 1-year, phase IIIb/IV, randomized, triple-dummy, active-comparator-controlled study. MTX-inadequate responder patients received tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID plus MTX, or ADA 40 mg every other week plus MTX (1:1:1 randomization). Eligible patients age ≥50 years could opt to receive LZV 28 days before initiating study treatment. HZ incidence rates (IRs; patients with events per 100 patient-years) were calculated. Opportunistic HZ infections (multidermatomal/disseminated), serious HZ events, and LZV-related adverse events were monitored. RESULTS: In ORAL Strategy, 216 of 1,146 patients (18.8%) received LZV. Overall, 18 patients (1.6%) developed HZ (vaccinated: n = 3; nonvaccinated: n = 15). HZ IRs were 1.1 (95% confidence interval [95% CI] 0.3-2.9), 2.3 (95% CI 1.0-4.6), and 1.7 (95% CI 0.6-3.7) for tofacitinib monotherapy, tofacitinib plus MTX, and ADA plus MTX, respectively, and were generally similar between vaccinated and nonvaccinated patients. Three multidermatomal, 1 disseminated, and 2 serious HZ events occurred. No vaccinated patients had zoster-like lesions within 42 days of vaccination; 1 patient had vaccination-site erythema. CONCLUSION: LZV was well tolerated, and HZ IRs were generally similar between treatment groups and vaccinated versus nonvaccinated patients. However, ORAL Strategy was not powered for comparisons between vaccinated and nonvaccinated patients because <20% of all patients were vaccinated. Furthermore, LZV has been shown to be effective only in ~50% of individuals.

Real-World Comparative Effectiveness of Tofacitinib and Tumor Necrosis Factor Inhibitors as Monotherapy and Combination Therapy for Treatment of Rheumatoid Arthritis.

INTRODUCTION: No published studies exist comparing the effectiveness of tofacitinib with other advanced therapies for the treatment of rheumatoid arthritis (RA) in real-world clinical practice. Here, we report differences in effectiveness of tofacitinib compared with standard of care, tumor necrosis factor inhibitors (TNFi), with or without concomitant methotrexate (MTX), using US Corrona registry data. METHODS: This observational cohort study included RA patients receiving tofacitinib (from 6 November 2012; N = 558) or TNFi (from 1 November 2001; N = 8014) with or without MTX until 31 July 2016. Efficacy outcomes at 6 months included modified American College of Rheumatology 20% responses, Clinical Disease Activity Index (CDAI) and Pain. Outcomes were compared between patients receiving TNFi and tofacitinib with or without MTX and by line of therapy. Outcomes within therapy lines were compared using propensity-score matching; between-group differences were estimated using mixed-effects regression models. RESULTS: Patients receiving tofacitinib had longer RA duration and a greater proportion had previously received biologics than those receiving TNFi; other baseline characteristics were comparable. In patients receiving second- and third-line TNFi therapy, CDAI low disease activity/remission response rates were significantly better with concomitant MTX. Too few patients received tofacitinib as second line for meaningful assessment. No significant differences were observed in outcomes between tofacitinib as monotherapy and tofacitinib with concomitant MTX. CONCLUSIONS: In clinical practice, TNFi efficacy is improved with concomitant MTX in the second and third line. In the third/fourth line, patients are likely to achieve similar efficacy with tofacitinib monotherapy, or TNFi or tofacitinib in combination with MTX. FUNDING: Pfizer Inc.

A pooled analysis of the safety of tofacitinib as monotherapy or in combination with background conventional synthetic disease-modifying antirheumatic drugs in a Phase 3 rheumatoid arthritis population.

OBJECTIVE: This post-hoc, pooled analysis of Phase 3 studies of tofacitinib examined the safety of tofacitinib 5 and 10 mg twice daily (BID) when used as monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). METHODS: Pooled data from six double-blind, randomized controlled Phase 3 studies of tofacitinib 5 and 10 mg BID in patients with RA were analyzed for safety and stratified by administration as monotherapy (ORAL Solo: NCT00814307 and ORAL Start: NCT01039688) or in combination with csDMARDs (ORAL Sync: NCT00856544, ORAL Standard: NCT00853385, ORAL Scan: NCT00847613, and ORAL Step: NCT00960440), and by glucocorticoid use at baseline. Safety assessments included incidence rates (IRs) for serious adverse events (SAEs), discontinuations due to AEs, serious infection events, and herpes zoster (HZ), and were evaluated throughout the duration of the Phase 3 studies. RESULTS: In total, 3881 patients were included in the safety analysis (monotherapy studies: n = 1380; combination therapy studies: n = 2501). IRs for selected AEs of interest were generally numerically lower in patients who received tofacitinib 5 and 10 mg BID as monotherapy than as combination therapy (SAEs: IR [range] 6.21-6.72 versus IR 10.17-13.46; discontinuations due to AEs: IR 5.53-6.18 versus IR 10.80-11.01; serious infections: IR 1.57-1.66 versus IR 3.39-3.56; HZ: IR 1.95-2.93 versus IR 4.37-4.99, respectively), irrespective of tofacitinib dose or glucocorticoid use. There were too few patients and events within the placebo group to fully evaluate effect between combination therapy and monotherapy. CONCLUSIONS: Safety profiles were generally similar between patients receiving monotherapy and combination therapy; however, selected safety events of interest, including HZ and serious infections, showed lower IRs with non-overlapping 95% confidence intervals for tofacitinib all monotherapy versus combination therapy. Tofacitinib monotherapy may, therefore, have fewer safety events compared with combination therapy, and have a favorable risk-benefit profile in patients with active RA who are intolerant to csDMARDs.

Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and long-term outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background MTX. RAPID3 scores were calculated at baseline, month (M)6, and M24, and defined as remission (≤ 3), low (LDA; > 3-≤ 6), moderate (MDA; > 6-≤ 12), or high disease activity (HDA; > 12). Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and radiographic non-progression (modified Total Sharp Scores ≤ 0) at M24 were evaluated by M6 RAPID3 response. Among patients receiving tofacitinib 5 or 10 mg BID, respectively, 42.2 and 51.5% (ORAL Start) and 29.8 and 39.0% (ORAL Scan) achieved RAPID3 remission/LDA at M6. Most patients maintained/improved RAPID3 responses at M24. A higher proportion of patients in RAPID3 remission/LDA versus MDA/HDA at M6 achieved CDAI remission, reported normative HAQ-DI scores (< 0.5), and achieved both normative HAQ-DI scores and radiographic non-progression at M24. Patients achieving RAPID3 remission/LDA after 6-month treatment with tofacitinib 5 or 10 mg BID have improved long-term outcomes versus patients with MDA/HDA. These findings support the use of RAPID3 to monitor longer-term disease activity in conjunction with physician-assessed measures.

Effect of Discontinuation or Initiation of Methotrexate or Glucocorticoids on Tofacitinib Efficacy in Patients with Rheumatoid Arthritis: A Post Hoc Analysis.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the effect of concomitant methotrexate (MTX) or glucocorticoid (GC) use on tofacitinib clinical efficacy. METHODS: Data were pooled from two open-label, long-term extension studies of tofacitinib 5 or 10 mg twice daily in patients with RA. Response according to Clinical Disease Activity Index (CDAI) was assessed separately in patients who discontinued (no MTX/GC use within 30 days prior to year-3 visit; assessment at month 3/year 3) or initiated (on/before year 3; assessment at initiation and year 3) MTX/GC. RESULTS: By year 3, among patients receiving background MTX at baseline, 186/1608 (11.6%) discontinued MTX, and 319/1434 (22.2%) patients receiving GC at baseline discontinued GC. Overall, 70.4/69.1% of patients who discontinued/continued MTX and 72.7/65.9% who discontinued/continued GC achieved CDAI remission or low disease activity (LDA) at year 3. Month 3 remission/LDA rates were maintained at year 3 in the majority of patients, irrespective of MTX/GC discontinuation/continuation. By year 3, 6.2% of patients receiving tofacitinib without MTX at baseline had initiated concomitant MTX, and 25.1% receiving tofacitinib without GC initiated GC; 69.0% and 45.4% initiating MTX or GC, respectively, had a CDAI-defined incomplete response prior to initiation. RA signs/symptoms improved following MTX initiation; only modest improvement was observed with GC initiation. CONCLUSIONS: Patients achieving remission/LDA with tofacitinib may discontinue MTX or GC and maintain treatment response. Patients with an incomplete response may benefit from adding concomitant MTX. FUNDING: Pfizer Inc. TRIAL REGISTRATION: Study A3921024 [NCT00413699] and Study A3921041 [NCT00661661].

Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. METHODS: ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than -13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. FINDINGS: 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI -6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (-6 [-14 to 3]) or tofacitinib and methotrexate (-8 [-16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. INTERPRETATION: Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. FUNDING: Pfizer Inc.

Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis.

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the efficacy and safety of tofacitinib 5 or 10 mg twice daily (BID), in patients with moderate to severe RA, aged ≥65 and <65 years. METHODS: Data were pooled from five Phase 3 trials and, separately, from two open-label long-term extension (LTE) studies (data cut-off April, 2012). Patients received tofacitinib, or placebo (Phase 3 only), with/without conventional synthetic DMARDs (mainly methotrexate). Clinical efficacy outcomes from Phase 3 studies were evaluated at Month 3. Safety evaluations using pooled Phase 3 data (Month 12) and pooled LTE data (Month 24) compared exposure-adjusted incidence rates (IRs; with 95% confidence intervals [CIs]), in older versus younger patients. RESULTS: In Phase 3 and LTE studies, 15.3% (475/3111) and 16.1% (661/4102) of patients, respectively, were aged ≥65 years. Consequently, exposure to tofacitinib was lower in older versus younger patients in Phase 3 (259.2 vs. 1554.9 patient years [pt-yrs]) and LTE (962.1 vs. 5071.7 pt-yrs) studies. Probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 (Month 3) favoured tofacitinib and were similar in older and younger patients, with overlapping CIs. IRs for SAEs and discontinuations due to AEs were generally numerically higher in older versus younger patients, irrespective of treatment. CONCLUSIONS: Older patients receiving tofacitinib 5 or 10 mg BID had a similar probability of ACR20 or ACR50 response and, due to comorbidities, a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients.

Safety and maintenance of response for tofacitinib monotherapy and combination therapy in rheumatoid arthritis: an analysis of pooled data from open-label long-term extension studies.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post hoc analysis evaluated patients receiving tofacitinib monotherapy or combination therapy, as well as those who switched from monotherapy to combination therapy (mono→combo) or vice versa (combo→mono) in long-term extension (LTE) studies. METHODS: Data were pooled from open-label LTE studies (ORAL Sequel (NCT00413699; ongoing; data collected 14 January 2016) and NCT00661661) involving patients who participated in qualifying index studies. Efficacy outcomes included American College of Rheumatology 20/50/70 rates, change from baseline in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index and DAS28-4(ESR) and CDAI low disease activity and remission. Safety was evaluated over 96 months. RESULTS: Of the 4967 patients treated, 35.4% initiated tofacitinib monotherapy, 64.6% initiated combination therapy, 2.6% were mono→combo switchers and 7.1% were combo→mono switchers. Patients who switched multiple times were excluded. Of those who initiated monotherapy and combination therapy, 87.8% (1543/1757) and 82.0% (2631/3210), respectively, remained on the same regimen throughout the study; efficacy was maintained. Incidence rates (IRs) for serious adverse events with tofacitinib 5 mg and 10 mg twice daily, respectively, were 9.42 and 8.41 with monotherapy and 8.36 and 10.75 with combination therapy; IRs for discontinuations due to AEs were 7.13 and 6.06 with monotherapy and 7.82 and 8.06 with combination therapy (overlapping CIs). For mono→combo and combo→mono switchers, discontinuations due to AEs were experienced by 0.8% and 0.9%, respectively, within 30 days of switching. CONCLUSION: Tofacitinib efficacy as monotherapy or combination therapy was maintained through month 48 and sustained to month 72, with minimal switching of treatment regimens. Safety was consistent over 96 months. CLINICAL TRIAL REGISTRATION: NCT00413699 (Pre-results) and NCT00661661 (Results).