- Email: [email protected]
398 Efficacy and safety of ixekizumab for the treatment of plaque psoriasis: Results through 108 weeks randomised, phase III clinical trial (UNCOVER-3)
ABSTRACTS | Inflammation, Immunity and Infection 394
395
Analysis of keratinocyte response to Trichophyton rubrum dermatophyte infection in a model of reconstructed human epidermis E Faway1, L Cambier2, C Lambert de Rouvroit1, B Mignon2 and Y Poumay1 1 URPhyMNARILIS, University of Namur, Namur, Belgium and 2 FARAH, University of Lie`ge, Lie`ge, Belgium Dermatophytosis is a superficial fungal infection of keratinized structures. Its incidence is estimated around 20% in the global human population and has increased during the last decade. Despite such threatening incidence, precise information is still lacking about keratinocyte responses devoted to alert immune components and fight against infection. In order to identify and characterize such responses, fungal infection of reconstructed human epidermis (RHE) was undertaken. Arthrospores of the anthropophilic Trichophyton rubrum dermatophyte were topically seeded on RHE. Infected tissue was then maintained for 4 days in culture. Levels of expression and release of pro-inflammatory cytokines and antimicrobial peptides by keratinocytes were respectively assessed by RT-qPCR on RNA from tissue extracts and by ELISA on culture media. Integrity of the epidermal barrier was monitored using measurement of trans-epithelial electrical resistance or of dye-permeation through the RHE using Lucifer Yellow. During the first 3 days of infection, no response can be detected using these assays. On the fourth day after inoculating RHE with pathogens, cytokines (TNFa, IL-8, TSLP) are revealed in culture media and levels of mRNA encoding cytokines (TSLP, IL-1a, IL1b, IL-8) or antimicrobial peptides (b-defensin-2, b-defensin-3, S100A7) are increased in keratinocytes. Simultaneously, the epidermal barrier of the RHE weakens. Altogether, these results suggest that dermatophytes inoculated on RHE initially remain confined inside the stratum corneum for 3 days after starting the infection, likely blocked in the superficial layer by an efficient barrier. On the fourth day, dermatophyte infection results into a barrier disruption in the RHE by a still unknown mechanism. Alteration of the epidermal barrier, allowing intimate contact between fungal processes and living keratinocytes, appears responsible for activation of epidermal, as well as immune defenses.
In vitro expansion of desmoglein-specific B cells of patients with pemphigus H Suga1,2, S Mallam3, R Streilein3, T Tedder2 and R Hall3 1 Dermatology, University of Tokyo, Tokyo, Japan, 2 Immunology, Duke University Medical Center, Durham, NC and 3 Dermatology, Duke University Medical Center, Durham, NC The ability to expand B cells in vitro has become a useful tool for studying human immunity. We have developed a culture system to support the expansion of human mature B cells purified from peripheral blood. Murine bone marrow stromal cell line MS-5 was used as feeder cells to support the growth of human B cells. Single B cells expanded by 46,689 4,105 (mean s.e.m.) fold after 12 days of culture. The monoclonal IgM and IgG levels in the culture supernatant were 9.3 1.4 mg/mL and 10.5 0.8 mg/mL, respectively, which could be readily screened by ELISA. Pemphigus vulgaris (PV) and foliaceus (PF) are severe blistering diseases of the skin that are caused by autoantibodies directed against desmoglein-1 (DSG1) and DSG3. Utilizing in vitro B cells expansion system made it possible to better understand the frequency of DSG1/ DSG3 specific B cells in PV/PF patients. B cells were isolated from patients with clinically active PV (n¼2), PF (n¼2) and healthy controls (HC) (n¼2). Peripheral blood B cells (10/well) were cultured in 96 well plates for 12 days. Supernatants were tested for the presence of DSG1 or DSG3 antibodies by ELISA. The frequency of wells with ELISA values outside of 3x the interquartile range (IQR) was calculated for each subject. Supernatants from pemphigus patients showed a higher frequency of wells producing IgG anti DSG1 or DSG3 than controls (Mean frequency of wells > 3x IQR: PV/PF ¼ 4. 87%; HC ¼ 1.89%, p ¼ 0.03). Indirect immunofluorescence staining with supernatants of high outlier wells showed intracellular IgG deposits in the epidermis, which are consistent with the pattern seen in the staining with serum of PV/PF patients. In conclusion, our culture system enabled us to identify and expand DSG-specific B cells, and to visualize an increase in frequency of DSGspecific B cells in peripheral blood of patients with active PV/PF.
396
397
Ixekizumab treatment shows a neutral impact on the glucose and lipid profile of patients with moderate-to-severe psoriasis: Results from UNCOVER-1,-2, and -3 JJ Wu1, A Egeberg2, JA Solomon3, O Osuntokun4, O Goldblum4, S Moriarty4, F Zhao4, N Korman5 and M Vincent4 1 Dermatology, Kaiser Permanente Los Angeles Medical Center, Oakland, CA, 2 Gentofte Hospital, Copenhagen, Denmark, 3 Ameriderm Research, Florida, FL, 4 Eli Lilly and Company, Indianapolis, IN and 5 University Hospitals Case Medical Center, Cleveland, OH Ixekizumab (IXE), a monoclonal high affinity antibody that selectively targets interleukin-17A, is highly efficacious in pts with moderate-to-severe psoriasis. The objective of this analysis is to examine cardiovascular-related parameters in pts treated with IXE. In phase 3, multicenter, double-blind, placebo (PBO)-controlled trials (UNCOVER-1,-2, -3), pts were randomised to receive subcutaneous PBO (N¼791) or 80mg IXE as 1 injection every 2 (IXEQ2W; N¼1167) or 4 weeks (wks) (IXEQ4W; N¼1161) for 12 wks (160mg IXE starting dose: induction period). At Wk 12, UNCOVER-1 and -2 responders (sPGA 0,1) to IXE treatment were treated with PBO (N¼402) or IXEQ4W (N¼416) up to Wk 60 (maintenance period). Summary results are reported as mean change from baseline (CFB; Week 0) for: fasting serum glucose, serum total cholesterol, serum low-density lipoprotein (LDL), serum high-density lipoprotein (HDL), serum triglyceride, and LDL/HDL ratio. Mean (SD) change from baseline (CFB) to endpoint (mg/dL) in the induction period for IXEQ2W, IXEQ4W, and PBO were: fasting glucose 0.8 (21.5), 1.7 (22.7), and 1.1(27.2); total cholesterol 3.7 (25.5), 3.4 (27.5), and -1.6 (24.8); LDL 2.5 (22.0), 1.8 (22.6), and -1.0 (21.3); HDL 0.5 (8.2), 0.1 (8.0), and 0 (7.9); triglycerides 2.6 (79.3), 9.5 (81.8), and -0.5 (77.1); and LDL/HDL ratio 0.02 (1.1), 0.03 (0.5), and -0.03 (0.5). Mean CFB (Wk 0;SD)(mg/dL) at Wk 60 for IXEQ4W and PBO were: fasting glucose 0.4 (21.1) and 0.7 (14.3); total cholesterol -1.0 (26.0) and -2.0 (25.7); LDL -1.0 (21.7) and 0 (22.3); HDL 0.1 (8.8) and -0.3 (7.8); triglycerides 10.8 (91.9) and 14.2 (87.6) and LDL/HDL ratio -0.07 (0.5) and 0.02 (0.4). Ixekizumab appears to have a neutral effect on glucose and lipid profiles in pts with moderate-to-severe plaque psoriasis.
Fifty two-week efficacy and safety results from SPIRIT-P1: A Phase 3 study of ixekizumab in patients with active psoriatic arthritis P Mease1, M Okada2, M Kishimoto2, C Shuler3, H Carlier3, C Lin3, J Mou3, SR Moriarty3, C Lee3, D Gladman4 and M Satler (non-author presenter)5 1 Swedish Medical Center and University of Washington, Seattle, WA, 2 St Luke’s International Hospital, Tokyo, Japan, 3 Eli Lilly and Company, Indianapolis, IN, 4 University of Toronto, Toronto, ON, Canada and 5 Eli Lilly Regional Operations GmbH, Vienna, Austria The efficacy and safety of ixekizumab were evaluated in patients with active PsA. Patients (N¼417) were randomised to ixekizumab 80mg once every 4 (IXEQ4W) or 2 (IXEQ2W) weeks (160mg starting dose included), 40mg adalimumab, or placebo during the doubleblind treatment period (weeks 0e24). 381 patients entered the extension period (weeks 24e52): at week 16 or 24, patients from the adalimumab or placebo groups were re-randomised to IXEQ4W or IXEQ2W. Results are presented for the extension period population who received IXEQ4W or IXEQ2W since baseline (IXEQ4W/IXEQ4W and IXEQ2W/ IXEQ2W). The extension period was completed by 304 patients. Response rates at week 52 for the groups, respectively, were: ACR 20/50/70: 69.1/54.6/39.2%, 68.8/53.1/39.6%; PASI 75/90/100: 78.8/66.7/56.1%, 81.8/78.2/67.3%; static PGA score of (0 or 1)/(0): 81.3/60.4%, 78.4/62.2%. For the IXEQ4W/IXEQ4W and IXEQ2W/IXEQ2W groups, respectively, changes from baseline to week 52 were -13.5 and -9.3 for percent BSA involvement of psoriasis and -16.5 and -21.6 for NAPSI. Most adverse events (AEs) were mild or moderate; serious AEs occurred in 4 patients. Ixekizumab demonstrated improvements in signs and symptoms of PsA with a safety profile that was consistent in the extension period and double-blind treatment period.
398
399
Efficacy and safety of ixekizumab for the treatment of plaque psoriasis: Results through 108 weeks randomised, phase III clinical trial (UNCOVER-3) A Blauvelt3,1, M Gooderham5, L Iversen2, S Ball3, L Zhang3, N Agada3, K Reich4 and M Dossenbach (non author presenter)3 1 Oregon Medical Research Center, Portland, OR, 2 Aarhus University Hospital, Aarhus, Denmark, 3 Eli Lilly and Company, Indianapolis, IN, 4 Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany and 5 SKIN Centre for Dermatology and Queen’s University, Portland, OR Ixekizumab (IXE) has shown efficacy in patients (pts) with moderate-to-severe plaque psoriasis through 60 weeks (wks). We report the efficacy and safety of IXE through 108 wks (UNCOVER-3). Pts (N¼1346) were randomised to 80mg IXE every 2 (IXEQ2W) or 4 wks (IXEQ4W) (160mg starting dose), etanercept (ETN; 50mg twice wkly), or placebo (PBO) for 12-wk induction. Pts entered long-term extension (LTE) at wk 12. ETN or PBO pts received PBO or 160mg IXE, respectively, at wk 12, then IXEQ4W. All other pts received IXEQ4W at wk 12 and thereafter. Dosing could be increased to IXEQ2W after wk 60. Efficacy was measured by percentage of pts achieving PASI 75/90/100 and sPGA 0/1 or 0 (observed case [OC] and LOCF). 1100 pts (81.7%) completed wk 108. PASI 75/90/100 response rates (%) for each treatment arm (OC/LOCF) were: IXEQ2W/IXEQ4W, 93/80/56 and 84/71/49; IXEQ4W/ IXEQ4W, 92/81/58 and 82/72/51; PBO/IXEQ4W, 94/80/56 and 86/73/50; ETN/IXEQ4W, 94/ 86/61 and 85/76/53. At wk 108, sPGA 0/1 rates were 83%/74% (OC/LOCF); sPGA 0 rates were 57%/50% in IXEQ2W/IXEQ4W. 1274 pts entered LTE: 48 (3.8%) increased dosage to IXEQ2W. Cumulative rates of the most frequent (7.5%) treatment-emergent adverse events (TEAEs) during LTE were nasopharyngitis (23.5%), upper respiratory infection (7.5%), and injection site reactions (7.5%). Most TEAEs were mild/moderate. Cumulative rate of grade 3/4 neutropenia was 0.6% (one grade 4 event occurred at wk 108). Five deaths were reported, none considered related to IXE. Pts achieved similar response rates that remained consistently high through 108 wks of IXE treatment across all treatment arms. The 108-wk safety profile of IXE was comparable to shorter treatment periods.
S260 Journal of Investigative Dermatology (2017), Volume 137
IL-36 receptor antagonistic antibodies inhibit inflammatory response in IL-23 model of psoriasiform dermatitis V Todorovic1, Z Su1, S Lippert1, L Leys1, C Gerstein1, J Seagal2, S Mathew2, A Horowitz2, L Olson1, B Sielaff2, L Medina2, L Wang2, R Sadhukan2, K Salte1 and V Scott1 1 Dermatology, AbbVie, North Chicago, IL and 2 Discovery Biologics, AbbVie, Worcester, MA Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by skin responses. Among skin derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is scant data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein we interrogate if functional inhibition of IL-36 receptor (IL-36R) in the IL-23-induced mouse models of psoriasiform dermatitis drives down the skin inflammation. Anti-IL-36R antibodies (mAbs) were validated in vitro by inhibiting IL-36a induced secretion of mouse CXCL1 from NIH 3T3 cells. In vivo antibody target engagement was validated by inhibition of CXCL1 production in an acute model of IL-36a systemic injection. In addition, anti-IL-36R mAbs were able to inhibit tissue inflammation and inflammatory gene expression in an IL-36a ear injection model of psoriasiform dermatitis demonstrating adequate target coverage in the ear skin. To elucidate the possible role of IL-36 signaling in IL-23/Th17 pathway we tested the ability of anti-IL-36R mAbs to inhibit skin inflammation in both IL-23 ear injection and IL-23 mini-circle mouse models. We show that inhibiting IL-36 pathway results in significant but modest attenuation of skin thickening, inflammatory cell infiltration and psoriasis-relevant gene expression in both models. Taken together, our data suggests a role for IL-36 signaling in the IL-23/Th17 signaling axis in PV. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
395
Analysis of keratinocyte response to Trichophyton rubrum dermatophyte infection in a model of reconstructed human epidermis E Faway1, L Cambier2, C Lambert de Rouvroit1, B Mignon2 and Y Poumay1 1 URPhyMNARILIS, University of Namur, Namur, Belgium and 2 FARAH, University of Lie`ge, Lie`ge, Belgium Dermatophytosis is a superficial fungal infection of keratinized structures. Its incidence is estimated around 20% in the global human population and has increased during the last decade. Despite such threatening incidence, precise information is still lacking about keratinocyte responses devoted to alert immune components and fight against infection. In order to identify and characterize such responses, fungal infection of reconstructed human epidermis (RHE) was undertaken. Arthrospores of the anthropophilic Trichophyton rubrum dermatophyte were topically seeded on RHE. Infected tissue was then maintained for 4 days in culture. Levels of expression and release of pro-inflammatory cytokines and antimicrobial peptides by keratinocytes were respectively assessed by RT-qPCR on RNA from tissue extracts and by ELISA on culture media. Integrity of the epidermal barrier was monitored using measurement of trans-epithelial electrical resistance or of dye-permeation through the RHE using Lucifer Yellow. During the first 3 days of infection, no response can be detected using these assays. On the fourth day after inoculating RHE with pathogens, cytokines (TNFa, IL-8, TSLP) are revealed in culture media and levels of mRNA encoding cytokines (TSLP, IL-1a, IL1b, IL-8) or antimicrobial peptides (b-defensin-2, b-defensin-3, S100A7) are increased in keratinocytes. Simultaneously, the epidermal barrier of the RHE weakens. Altogether, these results suggest that dermatophytes inoculated on RHE initially remain confined inside the stratum corneum for 3 days after starting the infection, likely blocked in the superficial layer by an efficient barrier. On the fourth day, dermatophyte infection results into a barrier disruption in the RHE by a still unknown mechanism. Alteration of the epidermal barrier, allowing intimate contact between fungal processes and living keratinocytes, appears responsible for activation of epidermal, as well as immune defenses.
In vitro expansion of desmoglein-specific B cells of patients with pemphigus H Suga1,2, S Mallam3, R Streilein3, T Tedder2 and R Hall3 1 Dermatology, University of Tokyo, Tokyo, Japan, 2 Immunology, Duke University Medical Center, Durham, NC and 3 Dermatology, Duke University Medical Center, Durham, NC The ability to expand B cells in vitro has become a useful tool for studying human immunity. We have developed a culture system to support the expansion of human mature B cells purified from peripheral blood. Murine bone marrow stromal cell line MS-5 was used as feeder cells to support the growth of human B cells. Single B cells expanded by 46,689 4,105 (mean s.e.m.) fold after 12 days of culture. The monoclonal IgM and IgG levels in the culture supernatant were 9.3 1.4 mg/mL and 10.5 0.8 mg/mL, respectively, which could be readily screened by ELISA. Pemphigus vulgaris (PV) and foliaceus (PF) are severe blistering diseases of the skin that are caused by autoantibodies directed against desmoglein-1 (DSG1) and DSG3. Utilizing in vitro B cells expansion system made it possible to better understand the frequency of DSG1/ DSG3 specific B cells in PV/PF patients. B cells were isolated from patients with clinically active PV (n¼2), PF (n¼2) and healthy controls (HC) (n¼2). Peripheral blood B cells (10/well) were cultured in 96 well plates for 12 days. Supernatants were tested for the presence of DSG1 or DSG3 antibodies by ELISA. The frequency of wells with ELISA values outside of 3x the interquartile range (IQR) was calculated for each subject. Supernatants from pemphigus patients showed a higher frequency of wells producing IgG anti DSG1 or DSG3 than controls (Mean frequency of wells > 3x IQR: PV/PF ¼ 4. 87%; HC ¼ 1.89%, p ¼ 0.03). Indirect immunofluorescence staining with supernatants of high outlier wells showed intracellular IgG deposits in the epidermis, which are consistent with the pattern seen in the staining with serum of PV/PF patients. In conclusion, our culture system enabled us to identify and expand DSG-specific B cells, and to visualize an increase in frequency of DSGspecific B cells in peripheral blood of patients with active PV/PF.
396
397
Ixekizumab treatment shows a neutral impact on the glucose and lipid profile of patients with moderate-to-severe psoriasis: Results from UNCOVER-1,-2, and -3 JJ Wu1, A Egeberg2, JA Solomon3, O Osuntokun4, O Goldblum4, S Moriarty4, F Zhao4, N Korman5 and M Vincent4 1 Dermatology, Kaiser Permanente Los Angeles Medical Center, Oakland, CA, 2 Gentofte Hospital, Copenhagen, Denmark, 3 Ameriderm Research, Florida, FL, 4 Eli Lilly and Company, Indianapolis, IN and 5 University Hospitals Case Medical Center, Cleveland, OH Ixekizumab (IXE), a monoclonal high affinity antibody that selectively targets interleukin-17A, is highly efficacious in pts with moderate-to-severe psoriasis. The objective of this analysis is to examine cardiovascular-related parameters in pts treated with IXE. In phase 3, multicenter, double-blind, placebo (PBO)-controlled trials (UNCOVER-1,-2, -3), pts were randomised to receive subcutaneous PBO (N¼791) or 80mg IXE as 1 injection every 2 (IXEQ2W; N¼1167) or 4 weeks (wks) (IXEQ4W; N¼1161) for 12 wks (160mg IXE starting dose: induction period). At Wk 12, UNCOVER-1 and -2 responders (sPGA 0,1) to IXE treatment were treated with PBO (N¼402) or IXEQ4W (N¼416) up to Wk 60 (maintenance period). Summary results are reported as mean change from baseline (CFB; Week 0) for: fasting serum glucose, serum total cholesterol, serum low-density lipoprotein (LDL), serum high-density lipoprotein (HDL), serum triglyceride, and LDL/HDL ratio. Mean (SD) change from baseline (CFB) to endpoint (mg/dL) in the induction period for IXEQ2W, IXEQ4W, and PBO were: fasting glucose 0.8 (21.5), 1.7 (22.7), and 1.1(27.2); total cholesterol 3.7 (25.5), 3.4 (27.5), and -1.6 (24.8); LDL 2.5 (22.0), 1.8 (22.6), and -1.0 (21.3); HDL 0.5 (8.2), 0.1 (8.0), and 0 (7.9); triglycerides 2.6 (79.3), 9.5 (81.8), and -0.5 (77.1); and LDL/HDL ratio 0.02 (1.1), 0.03 (0.5), and -0.03 (0.5). Mean CFB (Wk 0;SD)(mg/dL) at Wk 60 for IXEQ4W and PBO were: fasting glucose 0.4 (21.1) and 0.7 (14.3); total cholesterol -1.0 (26.0) and -2.0 (25.7); LDL -1.0 (21.7) and 0 (22.3); HDL 0.1 (8.8) and -0.3 (7.8); triglycerides 10.8 (91.9) and 14.2 (87.6) and LDL/HDL ratio -0.07 (0.5) and 0.02 (0.4). Ixekizumab appears to have a neutral effect on glucose and lipid profiles in pts with moderate-to-severe plaque psoriasis.
Fifty two-week efficacy and safety results from SPIRIT-P1: A Phase 3 study of ixekizumab in patients with active psoriatic arthritis P Mease1, M Okada2, M Kishimoto2, C Shuler3, H Carlier3, C Lin3, J Mou3, SR Moriarty3, C Lee3, D Gladman4 and M Satler (non-author presenter)5 1 Swedish Medical Center and University of Washington, Seattle, WA, 2 St Luke’s International Hospital, Tokyo, Japan, 3 Eli Lilly and Company, Indianapolis, IN, 4 University of Toronto, Toronto, ON, Canada and 5 Eli Lilly Regional Operations GmbH, Vienna, Austria The efficacy and safety of ixekizumab were evaluated in patients with active PsA. Patients (N¼417) were randomised to ixekizumab 80mg once every 4 (IXEQ4W) or 2 (IXEQ2W) weeks (160mg starting dose included), 40mg adalimumab, or placebo during the doubleblind treatment period (weeks 0e24). 381 patients entered the extension period (weeks 24e52): at week 16 or 24, patients from the adalimumab or placebo groups were re-randomised to IXEQ4W or IXEQ2W. Results are presented for the extension period population who received IXEQ4W or IXEQ2W since baseline (IXEQ4W/IXEQ4W and IXEQ2W/ IXEQ2W). The extension period was completed by 304 patients. Response rates at week 52 for the groups, respectively, were: ACR 20/50/70: 69.1/54.6/39.2%, 68.8/53.1/39.6%; PASI 75/90/100: 78.8/66.7/56.1%, 81.8/78.2/67.3%; static PGA score of (0 or 1)/(0): 81.3/60.4%, 78.4/62.2%. For the IXEQ4W/IXEQ4W and IXEQ2W/IXEQ2W groups, respectively, changes from baseline to week 52 were -13.5 and -9.3 for percent BSA involvement of psoriasis and -16.5 and -21.6 for NAPSI. Most adverse events (AEs) were mild or moderate; serious AEs occurred in 4 patients. Ixekizumab demonstrated improvements in signs and symptoms of PsA with a safety profile that was consistent in the extension period and double-blind treatment period.
398
399
Efficacy and safety of ixekizumab for the treatment of plaque psoriasis: Results through 108 weeks randomised, phase III clinical trial (UNCOVER-3) A Blauvelt3,1, M Gooderham5, L Iversen2, S Ball3, L Zhang3, N Agada3, K Reich4 and M Dossenbach (non author presenter)3 1 Oregon Medical Research Center, Portland, OR, 2 Aarhus University Hospital, Aarhus, Denmark, 3 Eli Lilly and Company, Indianapolis, IN, 4 Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany and 5 SKIN Centre for Dermatology and Queen’s University, Portland, OR Ixekizumab (IXE) has shown efficacy in patients (pts) with moderate-to-severe plaque psoriasis through 60 weeks (wks). We report the efficacy and safety of IXE through 108 wks (UNCOVER-3). Pts (N¼1346) were randomised to 80mg IXE every 2 (IXEQ2W) or 4 wks (IXEQ4W) (160mg starting dose), etanercept (ETN; 50mg twice wkly), or placebo (PBO) for 12-wk induction. Pts entered long-term extension (LTE) at wk 12. ETN or PBO pts received PBO or 160mg IXE, respectively, at wk 12, then IXEQ4W. All other pts received IXEQ4W at wk 12 and thereafter. Dosing could be increased to IXEQ2W after wk 60. Efficacy was measured by percentage of pts achieving PASI 75/90/100 and sPGA 0/1 or 0 (observed case [OC] and LOCF). 1100 pts (81.7%) completed wk 108. PASI 75/90/100 response rates (%) for each treatment arm (OC/LOCF) were: IXEQ2W/IXEQ4W, 93/80/56 and 84/71/49; IXEQ4W/ IXEQ4W, 92/81/58 and 82/72/51; PBO/IXEQ4W, 94/80/56 and 86/73/50; ETN/IXEQ4W, 94/ 86/61 and 85/76/53. At wk 108, sPGA 0/1 rates were 83%/74% (OC/LOCF); sPGA 0 rates were 57%/50% in IXEQ2W/IXEQ4W. 1274 pts entered LTE: 48 (3.8%) increased dosage to IXEQ2W. Cumulative rates of the most frequent (7.5%) treatment-emergent adverse events (TEAEs) during LTE were nasopharyngitis (23.5%), upper respiratory infection (7.5%), and injection site reactions (7.5%). Most TEAEs were mild/moderate. Cumulative rate of grade 3/4 neutropenia was 0.6% (one grade 4 event occurred at wk 108). Five deaths were reported, none considered related to IXE. Pts achieved similar response rates that remained consistently high through 108 wks of IXE treatment across all treatment arms. The 108-wk safety profile of IXE was comparable to shorter treatment periods.
S260 Journal of Investigative Dermatology (2017), Volume 137
IL-36 receptor antagonistic antibodies inhibit inflammatory response in IL-23 model of psoriasiform dermatitis V Todorovic1, Z Su1, S Lippert1, L Leys1, C Gerstein1, J Seagal2, S Mathew2, A Horowitz2, L Olson1, B Sielaff2, L Medina2, L Wang2, R Sadhukan2, K Salte1 and V Scott1 1 Dermatology, AbbVie, North Chicago, IL and 2 Discovery Biologics, AbbVie, Worcester, MA Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by skin responses. Among skin derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is scant data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein we interrogate if functional inhibition of IL-36 receptor (IL-36R) in the IL-23-induced mouse models of psoriasiform dermatitis drives down the skin inflammation. Anti-IL-36R antibodies (mAbs) were validated in vitro by inhibiting IL-36a induced secretion of mouse CXCL1 from NIH 3T3 cells. In vivo antibody target engagement was validated by inhibition of CXCL1 production in an acute model of IL-36a systemic injection. In addition, anti-IL-36R mAbs were able to inhibit tissue inflammation and inflammatory gene expression in an IL-36a ear injection model of psoriasiform dermatitis demonstrating adequate target coverage in the ear skin. To elucidate the possible role of IL-36 signaling in IL-23/Th17 pathway we tested the ability of anti-IL-36R mAbs to inhibit skin inflammation in both IL-23 ear injection and IL-23 mini-circle mouse models. We show that inhibiting IL-36 pathway results in significant but modest attenuation of skin thickening, inflammatory cell infiltration and psoriasis-relevant gene expression in both models. Taken together, our data suggests a role for IL-36 signaling in the IL-23/Th17 signaling axis in PV. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.