Dupilumab

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Diamant Thaçi - One of the best experts on this subject based on the ideXlab platform.

  • Dupilumab provides favourable long term safety and efficacy in children aged 6 to 12 years with uncontrolled severe atopic dermatitis results from an open label phase iia study and subsequent phase iii open label extension study
    British Journal of Dermatology, 2021
    Co-Authors: Michael J. Cork, Lawrence F. Eichenfield, Diamant Thaçi, Zhen Chen, Pd Arkwright, Xian Sun, B Akinlade, Susan Boklage, Isabelle Guillemin
    Abstract:

    BACKGROUND Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, Dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking. OBJECTIVES To report the pharmacokinetic profile and long-term safety and efficacy of Dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. METHODS Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose Dupilumab 2 or 4 mg kg-1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg-1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were Dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score. RESULTS Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized Dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg-1 , 61-77 mg L-1 ; 4 mg kg-1 , 143-181 mg L-1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg-1 , 47%; 4 mg kg-1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose Dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively. CONCLUSIONS These safety and efficacy results support the use of Dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.

  • efficacy and safety of Dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis a randomized double blinded placebo controlled phase 3 trial
    Journal of The American Academy of Dermatology, 2020
    Co-Authors: Michael J. Cork, Diamant Thaçi, Melinda Gooderham, Andreas Wollenberg, Amy S. Paller, Elaine C. Siegfried, Pd Arkwright, Lisa A. Beck
    Abstract:

    Background Children with severe atopic dermatitis (AD) have limited treatment options. Objective We report the efficacy and safety of Dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies. Methods In this double-blind, 16-week, phase 3 trial ( NCT03345914 ), 367 patients were randomized 1:1:1 to 300 mg Dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of Dupilumab every 2 weeks (100 mg q2w, baseline weight Results Both the q4w and q2w Dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal Dupilumab doses for efficacy and safety were 300 mg q4w in children Limitations Short-term 16-week treatment period; severe AD only. Conclusion Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL.

  • efficacy and safety of multiple Dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis a randomized clinical trial
    JAMA Dermatology, 2020
    Co-Authors: Margitta Worm, Eric L Simpson, Diamant Thaçi, M Kawashima, Robert Bissonnette, J P Lacour, Stefan Beissert, C Ferrandiz, Catherine Smith, Lisa A. Beck
    Abstract:

    Importance The Dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD). Objective To assess the efficacy and safety of different Dupilumab regimens in maintaining response after 16 weeks of initial treatment. Design, Setting, and Participants The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received Dupilumab treatment and achieved an Investigator’s Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous Dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016. Interventions High-responding patients treated with Dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of Dupilumab, 300 mg, weekly or every 2 weeks or to receive Dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks. Main Outcomes and Measures Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety. Results Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing Dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (−0.06%;P  Conclusions and Relevance In this trial, continued response over time was most consistently maintained with Dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of Dupilumab every 2 weeks is recommended for long-term treatment. Trial Registration ClinicalTrials.gov identifier:NCT02395133

  • Dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis results from a phase iia open label trial and subsequent phase iii open label extension
    British Journal of Dermatology, 2020
    Co-Authors: Michael J. Cork, Lawrence F. Eichenfield, Diamant Thaçi, John D. Davis, Zhen Chen, Thomas Hultsch, Pd Arkwright, Y Zhang, X Zhu, Marius Ardeleanu
    Abstract:

    Author(s): Cork, MJ; Thaci, D; Eichenfield, LF; Arkwright, PD; Hultsch, T; Davis, JD; Zhang, Y; Zhu, X; Chen, Z; Li, M; Ardeleanu, M; Teper, A; Akinlade, B; Gadkari, A; Eckert, L; Kamal, MA; Ruddy, M; Graham, NMH; Pirozzi, G; Stahl, N; DiCioccio, AT; Bansal, A | Abstract: BackgroundDupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428).ObjectivesTo characterize the pharmacokinetics of Dupilumab, and long-term safety and efficacy in adolescents.MethodsThis was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one Dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 Dupilumab weekly. Primary end points were Dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).ResultsForty adolescents received Dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough Dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one Dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )].ConclusionsIn adolescents with moderate-to-severe AD, Dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of Dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor α) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of Dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week Dupilumab phase III trial. The data from these studies also support the use of Dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.

  • Dupilumab provides important clinical benefits to patients with atopic dermatitis who do not achieve clear or almost clear skin according to the investigator s global assessment a pooled analysis of data from two phase iii trials
    British Journal of Dermatology, 2019
    Co-Authors: Jonathan I. Silverberg, Eric L Simpson, Diamant Thaçi, Andrew Korotzer, Laurent Eckert, Marius Ardeleanu, S Barbarot, Jerry Bagel, Z Chen, Jingdong Chao
    Abstract:

    Background In the U.S.A., an Investigator's Global Assessment (IGA) score of ≤ 1 (clear or almost clear skin) has been the standard measure in regulatory outcomes for registration clinical trials in atopic dermatitis (AD), including those supporting the recent approval of Dupilumab. Objectives To evaluate the treatment effect of Dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life. Methods LIBERTY AD SOLO 1 and 2 were two 16-week, randomized, double-blind trials enrolling adult patients with moderate-to-severe AD (IGA ≥ 3) inadequately controlled with topical treatment. We performed a post hoc analysis in patients receiving Dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA > 1 included Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), affected body surface area (BSA), Patient-Oriented Eczema Measure (POEM) and Dermatology Life Quality Index (DLQI). The trials were registered at ClinicalTrials.gov: NCT02277743 and NCT02277769. Results At week 16, 278 of 449 Dupilumab q2w-treated patients (median age 36·0 years) and 396 of 443 placebo-treated patients had IGA > 1. Among patients with IGA > 1 at week 16, Dupilumab significantly improved several outcome measures compared with placebo: EASI (-48·9% vs. -11·3%, P Conclusions In patients with IGA > 1 at week 16, Dupilumab induced statistically significant benefits in multiple validated outcome measures compared with placebo. The IGA ≤ 1 end point significantly underestimates clinically relevant Dupilumab treatment effects.

Eric L Simpson - One of the best experts on this subject based on the ideXlab platform.

  • laboratory safety of Dupilumab in moderate to severe atopic dermatitis results from three phase iii trials liberty ad solo 1 liberty ad solo 2 liberty ad chronos
    British Journal of Dermatology, 2020
    Co-Authors: Andreas Wollenberg, Andrew Blauvelt, Eric L Simpson, Lisa A. Beck, Zhen Chen, B Shumel, Q Chen, Faisal A Khokhar, Thomas Hultsch, E Rizova
    Abstract:

    BACKGROUND Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate-to-severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate-to-severe AD inadequately controlled with topical medications. OBJECTIVES To further characterize the safety of Dupilumab by evaluating clinical laboratory findings from three randomized, double-blinded, placebo-controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). METHODS Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to Dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. RESULTS Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in Dupilumab vs. placebo groups. Some Dupilumab-treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of Dupilumab-treated and placebo-treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during Dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. CONCLUSIONS There were no clinically important changes in routine laboratory parameters that could be attributed to Dupilumab. This study supports the use of Dupilumab as a systemic treatment for moderate-to-severe AD that does not require laboratory monitoring. What's already known about this topic? Long-term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side-effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities. Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for the treatment of patients with inadequately controlled, moderate-to-severe AD. In 16-week and 52-week studies, Dupilumab demonstrated a positive risk/benefit profile in moderate-to-severe AD. What does this study add? This study is the first comprehensive analysis of Dupilumab laboratory safety data of the 16-week SOLO 1 & 2 (pooled N = 1376) and 52-week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate-to-severe AD treated with Dupilumab. Our data support the use of Dupilumab as a systemic treatment for the long-term management of moderate-to-severe AD without routine laboratory monitoring in clinical practice.

  • efficacy and safety of multiple Dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis a randomized clinical trial
    JAMA Dermatology, 2020
    Co-Authors: Margitta Worm, Eric L Simpson, Diamant Thaçi, M Kawashima, Robert Bissonnette, J P Lacour, Stefan Beissert, C Ferrandiz, Catherine Smith, Lisa A. Beck
    Abstract:

    Importance The Dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD). Objective To assess the efficacy and safety of different Dupilumab regimens in maintaining response after 16 weeks of initial treatment. Design, Setting, and Participants The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received Dupilumab treatment and achieved an Investigator’s Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous Dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016. Interventions High-responding patients treated with Dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of Dupilumab, 300 mg, weekly or every 2 weeks or to receive Dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks. Main Outcomes and Measures Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety. Results Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing Dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (−0.06%;P  Conclusions and Relevance In this trial, continued response over time was most consistently maintained with Dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of Dupilumab every 2 weeks is recommended for long-term treatment. Trial Registration ClinicalTrials.gov identifier:NCT02395133

  • Dupilumab provides important clinical benefits to patients with atopic dermatitis who do not achieve clear or almost clear skin according to the investigator s global assessment a pooled analysis of data from two phase iii trials
    British Journal of Dermatology, 2019
    Co-Authors: Jonathan I. Silverberg, Eric L Simpson, Diamant Thaçi, Andrew Korotzer, Laurent Eckert, Marius Ardeleanu, S Barbarot, Jerry Bagel, Z Chen, Jingdong Chao
    Abstract:

    Background In the U.S.A., an Investigator's Global Assessment (IGA) score of ≤ 1 (clear or almost clear skin) has been the standard measure in regulatory outcomes for registration clinical trials in atopic dermatitis (AD), including those supporting the recent approval of Dupilumab. Objectives To evaluate the treatment effect of Dupilumab in patients with IGA > 1 at the end of treatment, using other validated outcome measures for AD signs, symptoms and quality of life. Methods LIBERTY AD SOLO 1 and 2 were two 16-week, randomized, double-blind trials enrolling adult patients with moderate-to-severe AD (IGA ≥ 3) inadequately controlled with topical treatment. We performed a post hoc analysis in patients receiving Dupilumab 300 mg every 2 weeks (q2w) or placebo. Outcome measures in patients with IGA > 1 included Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), affected body surface area (BSA), Patient-Oriented Eczema Measure (POEM) and Dermatology Life Quality Index (DLQI). The trials were registered at ClinicalTrials.gov: NCT02277743 and NCT02277769. Results At week 16, 278 of 449 Dupilumab q2w-treated patients (median age 36·0 years) and 396 of 443 placebo-treated patients had IGA > 1. Among patients with IGA > 1 at week 16, Dupilumab significantly improved several outcome measures compared with placebo: EASI (-48·9% vs. -11·3%, P Conclusions In patients with IGA > 1 at week 16, Dupilumab induced statistically significant benefits in multiple validated outcome measures compared with placebo. The IGA ≤ 1 end point significantly underestimates clinically relevant Dupilumab treatment effects.

  • Conjunctivitis in Dupilumab clinical trials.
    British Journal of Dermatology, 2019
    Co-Authors: Bolanle Akinlade, Michael J. Cork, Andrew Blauvelt, Emma Guttman-yassky, Marjolein S. De Bruin-weller, Penny A. Asbell, Esen K. Akpek, Eric L Simpson, Errol P Prens, Jonathan Corren
    Abstract:

    Background Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for Dupilumab vs. placebo. Objectives To characterize further the occurrence and risk factors of conjunctivitis in Dupilumab clinical trials. Methods We evaluated randomized placebo-controlled trials of Dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). Results In most AD trials, Dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued Dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both Dupilumab and placebo than in AD trials; Dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with Dupilumab treatment in most AD trials. In Dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for Dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in Dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most Dupilumab AD trials, Dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for Dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to Dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in Dupilumab-treated patients with AD.

  • efficacy and safety of Dupilumab monotherapy in adults with moderate to severe atopic dermatitis a pooled analysis of two phase 3 randomized trials liberty ad solo 1 and liberty ad solo 2
    Journal of Dermatological Science, 2019
    Co-Authors: Diamant Thaçi, Eric L Simpson, Abhijit Gadkari, Zhen Chen, Laurent Eckert, Neil M H Graham, M Deleuran, Yoko Kataoka, B Akinlade, Gianluca Pirozzi
    Abstract:

    Abstract Background Two phase 3 trials with identical design, LIBERTY AD SOLO 1 (NCT02277743) and LIBERTY AD SOLO 2 (NCT02277769), confirmed Dupilumab efficacy and safety versus placebo in adults with moderate-to-severe atopic dermatitis (AD). Objectives To report a pooled analysis of these trials to further explore Dupilumab’s effects on AD clinical parameters, patient-reported outcomes (PROs), symptoms of anxiety/depression, health-related quality of life (HRQoL), and safety. Methods A pooled analysis of two 16-week phase 3 studies in adults with moderate-to-severe AD (N = 1379) inadequately controlled with/inadvisable for topical medications, randomized to Dupilumab 300 mg once weekly (qw), every 2 weeks (q2w), or placebo. Results Dupilumab significantly improved all pre-specified efficacy endpoints versus placebo (P  Conclusions Dupilumab versus placebo significantly improved objective AD signs, subjective PROs, symptoms of anxiety/depression, and HRQoL, with a favorable benefit-risk profile in adults with moderate-to-severe AD.

Michael J. Cork - One of the best experts on this subject based on the ideXlab platform.

  • Dupilumab provides favourable long term safety and efficacy in children aged 6 to 12 years with uncontrolled severe atopic dermatitis results from an open label phase iia study and subsequent phase iii open label extension study
    British Journal of Dermatology, 2021
    Co-Authors: Michael J. Cork, Lawrence F. Eichenfield, Diamant Thaçi, Zhen Chen, Pd Arkwright, Xian Sun, B Akinlade, Susan Boklage, Isabelle Guillemin
    Abstract:

    BACKGROUND Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, Dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking. OBJECTIVES To report the pharmacokinetic profile and long-term safety and efficacy of Dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. METHODS Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose Dupilumab 2 or 4 mg kg-1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg-1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were Dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score. RESULTS Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized Dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg-1 , 61-77 mg L-1 ; 4 mg kg-1 , 143-181 mg L-1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg-1 , 47%; 4 mg kg-1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose Dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively. CONCLUSIONS These safety and efficacy results support the use of Dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.

  • efficacy and safety of Dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis a randomized double blinded placebo controlled phase 3 trial
    Journal of The American Academy of Dermatology, 2020
    Co-Authors: Michael J. Cork, Diamant Thaçi, Melinda Gooderham, Andreas Wollenberg, Amy S. Paller, Elaine C. Siegfried, Pd Arkwright, Lisa A. Beck
    Abstract:

    Background Children with severe atopic dermatitis (AD) have limited treatment options. Objective We report the efficacy and safety of Dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies. Methods In this double-blind, 16-week, phase 3 trial ( NCT03345914 ), 367 patients were randomized 1:1:1 to 300 mg Dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of Dupilumab every 2 weeks (100 mg q2w, baseline weight Results Both the q4w and q2w Dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal Dupilumab doses for efficacy and safety were 300 mg q4w in children Limitations Short-term 16-week treatment period; severe AD only. Conclusion Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL.

  • Dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis results from a phase iia open label trial and subsequent phase iii open label extension
    British Journal of Dermatology, 2020
    Co-Authors: Michael J. Cork, Lawrence F. Eichenfield, Diamant Thaçi, John D. Davis, Zhen Chen, Thomas Hultsch, Pd Arkwright, Y Zhang, X Zhu, Marius Ardeleanu
    Abstract:

    Author(s): Cork, MJ; Thaci, D; Eichenfield, LF; Arkwright, PD; Hultsch, T; Davis, JD; Zhang, Y; Zhu, X; Chen, Z; Li, M; Ardeleanu, M; Teper, A; Akinlade, B; Gadkari, A; Eckert, L; Kamal, MA; Ruddy, M; Graham, NMH; Pirozzi, G; Stahl, N; DiCioccio, AT; Bansal, A | Abstract: BackgroundDupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428).ObjectivesTo characterize the pharmacokinetics of Dupilumab, and long-term safety and efficacy in adolescents.MethodsThis was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one Dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 Dupilumab weekly. Primary end points were Dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).ResultsForty adolescents received Dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough Dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one Dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )].ConclusionsIn adolescents with moderate-to-severe AD, Dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of Dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor α) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of Dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week Dupilumab phase III trial. The data from these studies also support the use of Dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.

  • Conjunctivitis in Dupilumab clinical trials.
    British Journal of Dermatology, 2019
    Co-Authors: Bolanle Akinlade, Michael J. Cork, Andrew Blauvelt, Emma Guttman-yassky, Marjolein S. De Bruin-weller, Penny A. Asbell, Esen K. Akpek, Eric L Simpson, Errol P Prens, Jonathan Corren
    Abstract:

    Background Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for Dupilumab vs. placebo. Objectives To characterize further the occurrence and risk factors of conjunctivitis in Dupilumab clinical trials. Methods We evaluated randomized placebo-controlled trials of Dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). Results In most AD trials, Dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued Dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both Dupilumab and placebo than in AD trials; Dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with Dupilumab treatment in most AD trials. In Dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for Dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in Dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most Dupilumab AD trials, Dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for Dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to Dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in Dupilumab-treated patients with AD.

  • Dupilumab improves patient-reported symptoms of atopic dermatitis, symptoms of anxiety and depression, and health-related quality of life in moderate-to-severe atopic dermatitis: analysis of pooled data from the randomized trials SOLO 1 and SOLO 2.
    Journal of Dermatological Treatment, 2019
    Co-Authors: Michael J. Cork, Marjolein S. De Bruin-weller, Eric L Simpson, Giampiero Girolomoni, Laurent Eckert, Andreas Wollenberg, S Barbarot, April Armstrong, Luis Puig, Yoko Kataoka
    Abstract:

    Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled moderate-to-severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized. Objective: To evaluate the impact of Dupilumab on patient-reported AD symptoms and QoL. Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness. Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p < .05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p < .0001). At week 16, more Dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p < .0001). Limitations: Cultural differences of translated PROs. Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD.

Lisa A. Beck - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of Dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis a randomized double blinded placebo controlled phase 3 trial
    Journal of The American Academy of Dermatology, 2020
    Co-Authors: Michael J. Cork, Diamant Thaçi, Melinda Gooderham, Andreas Wollenberg, Amy S. Paller, Elaine C. Siegfried, Pd Arkwright, Lisa A. Beck
    Abstract:

    Background Children with severe atopic dermatitis (AD) have limited treatment options. Objective We report the efficacy and safety of Dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies. Methods In this double-blind, 16-week, phase 3 trial ( NCT03345914 ), 367 patients were randomized 1:1:1 to 300 mg Dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of Dupilumab every 2 weeks (100 mg q2w, baseline weight Results Both the q4w and q2w Dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal Dupilumab doses for efficacy and safety were 300 mg q4w in children Limitations Short-term 16-week treatment period; severe AD only. Conclusion Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL.

  • laboratory safety of Dupilumab in moderate to severe atopic dermatitis results from three phase iii trials liberty ad solo 1 liberty ad solo 2 liberty ad chronos
    British Journal of Dermatology, 2020
    Co-Authors: Andreas Wollenberg, Andrew Blauvelt, Eric L Simpson, Lisa A. Beck, Zhen Chen, B Shumel, Q Chen, Faisal A Khokhar, Thomas Hultsch, E Rizova
    Abstract:

    BACKGROUND Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate-to-severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate-to-severe AD inadequately controlled with topical medications. OBJECTIVES To further characterize the safety of Dupilumab by evaluating clinical laboratory findings from three randomized, double-blinded, placebo-controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). METHODS Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to Dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. RESULTS Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in Dupilumab vs. placebo groups. Some Dupilumab-treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of Dupilumab-treated and placebo-treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during Dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. CONCLUSIONS There were no clinically important changes in routine laboratory parameters that could be attributed to Dupilumab. This study supports the use of Dupilumab as a systemic treatment for moderate-to-severe AD that does not require laboratory monitoring. What's already known about this topic? Long-term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side-effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities. Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for the treatment of patients with inadequately controlled, moderate-to-severe AD. In 16-week and 52-week studies, Dupilumab demonstrated a positive risk/benefit profile in moderate-to-severe AD. What does this study add? This study is the first comprehensive analysis of Dupilumab laboratory safety data of the 16-week SOLO 1 & 2 (pooled N = 1376) and 52-week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate-to-severe AD treated with Dupilumab. Our data support the use of Dupilumab as a systemic treatment for the long-term management of moderate-to-severe AD without routine laboratory monitoring in clinical practice.

  • efficacy and safety of multiple Dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis a randomized clinical trial
    JAMA Dermatology, 2020
    Co-Authors: Margitta Worm, Eric L Simpson, Diamant Thaçi, M Kawashima, Robert Bissonnette, J P Lacour, Stefan Beissert, C Ferrandiz, Catherine Smith, Lisa A. Beck
    Abstract:

    Importance The Dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD). Objective To assess the efficacy and safety of different Dupilumab regimens in maintaining response after 16 weeks of initial treatment. Design, Setting, and Participants The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received Dupilumab treatment and achieved an Investigator’s Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous Dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016. Interventions High-responding patients treated with Dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of Dupilumab, 300 mg, weekly or every 2 weeks or to receive Dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks. Main Outcomes and Measures Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety. Results Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing Dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (−0.06%;P  Conclusions and Relevance In this trial, continued response over time was most consistently maintained with Dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of Dupilumab every 2 weeks is recommended for long-term treatment. Trial Registration ClinicalTrials.gov identifier:NCT02395133

  • Dupilumab treatment in adults with moderate to severe atopic dermatitis
    The New England Journal of Medicine, 2014
    Co-Authors: Lisa A. Beck, Thomas Bieber, Diamant Thaçi, Jennifer D. Hamilton, Jeffrey Ming, Neil M H Graham, Ross E Rocklin, Haobo Ren, Richard Kao, Eric L Simpson
    Abstract:

    BACKGROUND Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by Dupilumab of these key drivers of type 2 helper T-cell (Th2)–mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator’s global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS In the 4-week monotherapy studies, Dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of Dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the Dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the Dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator’s global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the Dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the Dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P = 0.002), despite the fact that patients who received Dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P = 0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with Dupilumab. CONCLUSIONS Patients treated with Dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not doselimiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.)

Zhen Chen - One of the best experts on this subject based on the ideXlab platform.

  • Dupilumab provides favourable long term safety and efficacy in children aged 6 to 12 years with uncontrolled severe atopic dermatitis results from an open label phase iia study and subsequent phase iii open label extension study
    British Journal of Dermatology, 2021
    Co-Authors: Michael J. Cork, Lawrence F. Eichenfield, Diamant Thaçi, Zhen Chen, Pd Arkwright, Xian Sun, B Akinlade, Susan Boklage, Isabelle Guillemin
    Abstract:

    BACKGROUND Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, Dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking. OBJECTIVES To report the pharmacokinetic profile and long-term safety and efficacy of Dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. METHODS Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose Dupilumab 2 or 4 mg kg-1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg-1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were Dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score. RESULTS Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized Dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg-1 , 61-77 mg L-1 ; 4 mg kg-1 , 143-181 mg L-1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg-1 , 47%; 4 mg kg-1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose Dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively. CONCLUSIONS These safety and efficacy results support the use of Dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.

  • laboratory safety of Dupilumab in moderate to severe atopic dermatitis results from three phase iii trials liberty ad solo 1 liberty ad solo 2 liberty ad chronos
    British Journal of Dermatology, 2020
    Co-Authors: Andreas Wollenberg, Andrew Blauvelt, Eric L Simpson, Lisa A. Beck, Zhen Chen, B Shumel, Q Chen, Faisal A Khokhar, Thomas Hultsch, E Rizova
    Abstract:

    BACKGROUND Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate-to-severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate-to-severe AD inadequately controlled with topical medications. OBJECTIVES To further characterize the safety of Dupilumab by evaluating clinical laboratory findings from three randomized, double-blinded, placebo-controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). METHODS Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to Dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. RESULTS Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in Dupilumab vs. placebo groups. Some Dupilumab-treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of Dupilumab-treated and placebo-treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during Dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. CONCLUSIONS There were no clinically important changes in routine laboratory parameters that could be attributed to Dupilumab. This study supports the use of Dupilumab as a systemic treatment for moderate-to-severe AD that does not require laboratory monitoring. What's already known about this topic? Long-term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side-effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities. Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for the treatment of patients with inadequately controlled, moderate-to-severe AD. In 16-week and 52-week studies, Dupilumab demonstrated a positive risk/benefit profile in moderate-to-severe AD. What does this study add? This study is the first comprehensive analysis of Dupilumab laboratory safety data of the 16-week SOLO 1 & 2 (pooled N = 1376) and 52-week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate-to-severe AD treated with Dupilumab. Our data support the use of Dupilumab as a systemic treatment for the long-term management of moderate-to-severe AD without routine laboratory monitoring in clinical practice.

  • Dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis results from a phase iia open label trial and subsequent phase iii open label extension
    British Journal of Dermatology, 2020
    Co-Authors: Michael J. Cork, Lawrence F. Eichenfield, Diamant Thaçi, John D. Davis, Zhen Chen, Thomas Hultsch, Pd Arkwright, Y Zhang, X Zhu, Marius Ardeleanu
    Abstract:

    Author(s): Cork, MJ; Thaci, D; Eichenfield, LF; Arkwright, PD; Hultsch, T; Davis, JD; Zhang, Y; Zhu, X; Chen, Z; Li, M; Ardeleanu, M; Teper, A; Akinlade, B; Gadkari, A; Eckert, L; Kamal, MA; Ruddy, M; Graham, NMH; Pirozzi, G; Stahl, N; DiCioccio, AT; Bansal, A | Abstract: BackgroundDupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428).ObjectivesTo characterize the pharmacokinetics of Dupilumab, and long-term safety and efficacy in adolescents.MethodsThis was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one Dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 Dupilumab weekly. Primary end points were Dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).ResultsForty adolescents received Dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough Dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one Dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )].ConclusionsIn adolescents with moderate-to-severe AD, Dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of Dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor α) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of Dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week Dupilumab phase III trial. The data from these studies also support the use of Dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.

  • efficacy and safety of Dupilumab monotherapy in adults with moderate to severe atopic dermatitis a pooled analysis of two phase 3 randomized trials liberty ad solo 1 and liberty ad solo 2
    Journal of Dermatological Science, 2019
    Co-Authors: Diamant Thaçi, Eric L Simpson, Abhijit Gadkari, Zhen Chen, Laurent Eckert, Neil M H Graham, M Deleuran, Yoko Kataoka, B Akinlade, Gianluca Pirozzi
    Abstract:

    Abstract Background Two phase 3 trials with identical design, LIBERTY AD SOLO 1 (NCT02277743) and LIBERTY AD SOLO 2 (NCT02277769), confirmed Dupilumab efficacy and safety versus placebo in adults with moderate-to-severe atopic dermatitis (AD). Objectives To report a pooled analysis of these trials to further explore Dupilumab’s effects on AD clinical parameters, patient-reported outcomes (PROs), symptoms of anxiety/depression, health-related quality of life (HRQoL), and safety. Methods A pooled analysis of two 16-week phase 3 studies in adults with moderate-to-severe AD (N = 1379) inadequately controlled with/inadvisable for topical medications, randomized to Dupilumab 300 mg once weekly (qw), every 2 weeks (q2w), or placebo. Results Dupilumab significantly improved all pre-specified efficacy endpoints versus placebo (P  Conclusions Dupilumab versus placebo significantly improved objective AD signs, subjective PROs, symptoms of anxiety/depression, and HRQoL, with a favorable benefit-risk profile in adults with moderate-to-severe AD.

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