Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PF-06817024 in Healthy Participants, Participants with Chronic Rhinosinusitis with Nasal Polyps, and Participants with Atopic Dermatitis: A Phase 1, Randomized, Double-Blind, Placebo-Controll
PF-06817024 is a high affinity, humanized antibody that binds interleukin-33, a proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream type 2 inflammation. This Phase 1, randomized, placebo-controlled study was conducted in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of escalating single and limited repeat PF-06817024 doses in healthy participants (Part 1), a single dose of PF-06817024 in participants with chronic rhinosinusitis with nasal polyps (Part 2), and repeat doses of PF-06817024 in participants with moderate to severe atopic dermatitis (atoptic dermatitis; Part 3). PF-06817024 was generally well tolerated in all participant populations. Most participants experienced a treatment-emergent adverse event (healthy participants, 78.4% and 100%; participants with chronic rhinosinusitis with nasal polyps, 90.9% and 88.9%; and participants with atoptic dermatitis, 60.0% and 62.5% in the PF-06817024 and placebo groups, respectively). No substantial deviations from dose proportionality were observed for single intravenous doses of 10-1000 mg, indicating linear PK in healthy participants. Mean terminal half-life ranged from 83 to 94 days after single intravenous administration in healthy participants and was similar to that observed after administration in the studied patient populations. Incidences of antidrug antibodies in the studied populations were 10.8%, 9.1%, and 5.0% for healthy participants, participants with chronic rhinosinusitis with nasal polyps, and participants with atoptic dermatitis, respectively. In addition, dose-dependent increases were observed in total serum interleukin-33 levels of treated participants, indicating target engagement. Overall, the PK and safety profile of PF-06817024 supports further investigation of the drug as a potential treatment for allergic diseases.
Danto SI
，Tsamandouras N
，Reddy P
，Gilbert S
，Mancuso J
，Page K
，Peeva E
，Vincent MS
，Beebe JS
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Efficacy and Safety of Abrocitinib in Patients with Severe and/or Difficult-to-Treat Atopic Dermatitis: A Post Hoc Analysis of the Randomized Phase 3 JADE COMPARE Trial.
Traditional systemic immunosuppressants and advanced therapies improve signs and symptoms of moderate-to-severe atopic dermatitis (AD). However, data are limited in severe and/or difficult-to-treat AD. In the phase 3 JADE COMPARE trial of patients with moderate-to-severe AD receiving background topical therapy, once-daily abrocitinib 200 mg and 100 mg showed significantly greater reductions in the symptoms of AD than placebo and significantly greater improvement in itch response (with abrocitinib 200 mg) than dupilumab at week 2.
This study assessed the efficacy and safety of abrocitinib and dupilumab in a subset of patients with severe and/or difficult-to-treat AD in a post hoc analysis of the JADE COMPARE trial.
Adults with moderate-to-severe AD received once-daily oral abrocitinib 200 mg or 100 mg, dupilumab 300 mg subcutaneous injection every 2 weeks, or placebo with concomitant medicated topical therapy. Severe and/or difficult-to-treat AD subgroups were classified by baseline characteristics [Investigator's Global Assessment (IGA) 4, Eczema Area and Severity Index (EASI) > 21, failure or intolerance to prior systemic agents (excluding patients who took only corticosteroids), percentage of body surface area (%BSA) > 50, upper quartiles of EASI (EASI > 38) and %BSA (%BSA > 65), and combined subgroup of IGA 4, EASI > 21, and %BSA > 50, and failure or intolerance to prior systemic agents (excluding patients who took only corticosteroids)]. Assessments included IGA score of 0 (clear) or 1 (almost clear) and a ≥ 2-point improvement from baseline, ≥ 75% and ≥ 90% improvement from baseline in EASI (EASI-75 and EASI-90), ≥ 4-point improvement from baseline in Peak Pruritus-Numerical Rating Scale (PP-NRS4), time to PP-NRS4, least squares mean (LSM) change from baseline in 14-day PP-NRS (days 2-15), Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI) up to week 16.
The proportion of patients achieving IGA 0/1, EASI-75, and EASI-90 responses was significantly greater with abrocitinib 200 mg than placebo (nominal p < 0.05) across all subgroups with severe and/or difficult-to-treat AD. Across most subgroups, PP-NRS4 response was significantly greater with abrocitinib 200 mg than placebo (nominal p < 0.01); the time to achieve this response was shorter with abrocitinib 200 mg (range 4.5-6.0 days) than abrocitinib 100 mg (range 5.0-17.0 days), dupilumab (range 8.0-11.0 days), and placebo (range 3.0-11.5 days). LSM change from baseline in POEM and DLQI was significantly greater with abrocitinib 200 mg than placebo (nominal p < 0.001) across all subgroups. Clinically meaningful differences were observed between abrocitinib and dupilumab for most evaluated endpoints across several subgroups, including in patients who failed or were intolerant to prior systemic therapy.
Abrocitinib provided rapid and substantially greater improvements in skin clearance and quality of life compared with placebo and dupilumab in subgroups of patients with severe and/or difficult-to-treat AD. These findings support the use of abrocitinib for severe and/or difficult-to-treat AD.
ClinicalTrials.gov, NCT03720470.
Simpson EL
，Silverberg JI
，Thyssen JP
，Viguier M
，Thaçi D
，de Bruin-Weller M
，Weidinger S
，Chan G
，DiBonaventura M
，Biswas P
，Feeney C
，Koulias C
，Cork MJ
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Dupilumab Provides Acceptable Safety and Sustained Efficacy for up to 4 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis.
Moderate-to-severe atopic dermatitis (AD) often requires long-term management with systemic therapies.
Our objective was to report the safety and efficacy of dupilumab treatment up to 4 years in adults with moderate-to-severe AD and efficacy in a subgroup of patients who transitioned from dupilumab once-weekly (qw) to administration every other week (q2w).
This interim analysis of the open-label extension study (NCT01949311) evaluated dupilumab 300 mg qw or q2w in adults previously enrolled in dupilumab trials for moderate-to-severe AD. Patients switched from qw to q2w following protocol amendment. The primary outcome was safety; efficacy was also assessed.
Of 2677 patients enrolled and treated, 352 (13.1%) completed week 204 (end of efficacy assessments) and 202 (7.5%) completed safety follow-up through week 244. Self-reported compliance was 98.1%. Dupilumab's safety profile was consistent with previous reports. Common treatment-emergent adverse events (≥5%) included nasopharyngitis, AD, upper respiratory tract infection, oral herpes, conjunctivitis, injection-site reaction, and headache. At week 204, mean ± standard deviation (SD) Eczema Area and Severity Index was 2.46 ± 3.98, and mean percent change from parent study baseline (PSBL) was -91.07%; mean ± SD Pruritus Numerical Rating Scale score was 2.10 ± 1.83, and mean percent change from PSBL was -68.74%. Efficacy was maintained in patients (n = 226) who transitioned from qw to q2w dosing. Limitations of this study included its open-label design, the lack of control arm, and smaller subsets of patients at later timepoints and receiving the approved q2w regimen.
These results support dupilumab as continuous long-term treatment for adults with moderate-to-severe AD; efficacy was sustained following transition from qw to q2w dosing. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01949311.
Beck LA
，Deleuran M
，Bissonnette R
，de Bruin-Weller M
，Galus R
，Nakahara T
，Seo SJ
，Khokhar FA
，Vakil J
，Xiao J
，Marco AR
，Levit NA
，O'Malley JT
，Shabbir A
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