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058 Efficacy of ixekizumab therapy: integrated analysis of 3 double-blind, controlled trials UNCOVER-1, UNCOVER-2, UNCOVER-3
ABSTRACTS | Clinical Outcomes 055
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Metabolomics analysis of sweat derived from atopic dermatitis by use of nuclear magnetic resonance E Ono1, H Murota1, Y Mori2, Y Yoshioka2 and I Katamaya1 1 Dermatology, Osaka University, Suita, Japan and 2 Osaka University, Suita, Japan Sweat has been considered as a major aggravating factor of atopic dermatitis (AD). Change in the contents of sweat may involve in pathogenesis of this disease. Sweat also includes both organic components and metabolites. There has been no knowledge about the difference in organic component between healthy subjects and AD patients. Thus, comprehensive analysis of metabolites in sweat was performed by use of nuclear magnetic resonance (NMR) in this study. Healthy subjects (n¼6, age range 28-45, mean 34, all male) were employed to this study. AD (n¼13, age range 17-50, mean 34, male: female, 10: 3) patients were chosen from inpatient. Sweat was induced by sauna bathing (80degree for 10-30 min), and is collected from the subjects back. NMR device used a 5mm Bruker broadband multinuclear probe using Bruker AVANCEII 2500MHz. NMR spectrum of the back sweat derived from healthy subjects were characterized by intense signals of lactate, pyruvate, and glycerol. Peak in glucose and hippuric acid were found specifically in sweat derived from subjects with AD. Sweat glucose concentration was measured by ELISA, and was divided into a low and a high glucose group. When comparing these two groups, SCORAD score tended to be high in high level of glucose group. Furthermore, glucose concentration were significantly correlated with SCORAD score (p¼0.0003). To clarify the mechanism of high glucose concentration in AD sweat, immunohistological analysis for glucose transporter such as GLUT or SGLT, which is known to play a substantial role in kidney, was performed, and we found GLUT2 expressed in the human sweat gland. Moreover, GLUT2 located in cytoplasm of secretory cells with appearance of granule in non-AD skin. On the other hand, in AD skin, GLUT2 located on the lumen of secretory cells. From these results, glucose in sweat might be a biomarker for severity of AD.
Impact of ixekizumab on palmoplantar plaque psoriasis compared to placebo and etanercept: results from UNCOVER 2 A Menter1, K Reich2, RB Warren3, KC Duffin4, R Langley5, L Kerr6, E Dennehy6, DS Shrom6 and D Amato6 1 University of Texas Southwestern Medical Center, Dallas, TX, 2 Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany, 3 University of Manchester, Salford, United Kingdom, 4 University of Utah, Sal Lake City, UT, 5 Dalhousie University, Halifax, NS, Canada and 6 Eli Lilly and Company, Indianapolis, IN Ixekizumab (IXE) is a high-affinity monoclonal antibody that selectively targets interleukin17A. In this analysis, the efficacy of IXE for psoriasis patients with moderate-to-severe palmoplantar involvement versus etanercept (ETN) and placebo (PBO) was evaluated. In the UNCOVER 2 trial, patients were randomized to PBO (N¼168), ETN (50 mg twice weekly; N¼358), or a single injection of 80 mg IXE every 2 weeks (IXE Q2W; N¼351) or every 4 weeks (IXE Q4W; N¼347) following a 160-mg starting dose at Week 0. Psoriatic involvement on hands and feet was assessed with the Palmoplantar Psoriasis Area and Severity Index (PPASI) (severity score range: 0 to 72). The percentage of patients with 100% reduction from baseline on the PPASI was analyzed in patients with baseline scores >¼8 (moderate-to-severe palmoplantar involvement). Treatment groups were compared using Cochran-MantelHaenszel test; missing data were imputed using non-responder imputation. At baseline, the percentage of patients with palmoplantar psoriasis in each treatment group was PBO, 32.7%; ETN, 26.5%; IXE Q2W, 29.6%; and IXE Q4W, 29.4%. Of those patients with PPASI scores >¼8 (n¼105), the overall mean (SD) baseline score was 19.4 (12.3). At 12 weeks, the percentage of patients within this population who had achieved 100% reduction in the PPASI score was statistically significantly greater with IXE Q2W (51.6% [n¼16 of 31], p<.001) and IXE Q4W (45.5% [n¼10 of 22], p¼.031) compared to PBO (5.6% [n¼1 of 18]). In addition, IXE Q2W showed superiority over ETN (29.4% [n¼10 of 34], p¼.039). There were no unexpected safety findings for patients treated with IXE. At Week 12, IXE was superior to PBO, and IXE Q2W was superior to ETN for 100% improvement in patients with moderate-tosevere palmoplantar plaque psoriasis.
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Detection of high-risk human papillomavirus DNA in cutaneous squamous cell carcinoma among young patients R Aoki, B Clanner-Engelshofen, B Feldner, L Birrou, T Ruzicka and M Reinholz Dermatology and Allergy, Ludwig-Maximilian-University, Munich, Germany High-risk mucosal a-Human papillomaviruses (a-HPV) are linked to cervical, anogenital and oropharyngeal cancers. Persistent infection with high-risk a-HPV can cause epithelial hyperplasia, leading to the development of squamous cell carcinoma. Additionally, cutaneous b-HPV are strongly associated with cutaneous squamous cell carcinoma (cSCC) in a specific group of patients and many recent studies have focused on the etiological role of b-HPV for cSCC and actinic keratosis (AK). However, the correlation between high-risk a-HPV and cSCC remains to be well defined, with previous reports showing conflicting results. In order to evaluate the possibility of high-risk a-HPV etiology for cSCC and AK, we compared HPV infections in cutaneous lesions obtained from young (under 60) or elderly (over 60) cSCC, AK patients and matched population controls. HPV detection was performed using polymerase chain reaction (PCR) in skin biopsies (24 young cSCC, 20 elderly cSCC, 32 AK and 10 normal young skins) and the DNA samples were used for HPV typing with DNA chip assay. Sixteen out of 24 (67%) skin lesions in young cSCC patients were found to be positive for high-risk a-HPV DNA and HPV type 16 were present in 94% of high-risk a-HPVpositive patients. HPV16 incidence was eight of 20 (40%) in elderly cSCC and one of 10 (10%) in the young normal skins. The higher prevalence of HPV16 in young cSCC patients suggests an association of HPV16 with cSCC especially among young population. High-risk a-HPV were detected more frequently in young cSCC samples from sun-exposed compared with non-exposed areas, implicating UV radiation as a possible risk factor for HPV detection. However, none of high-risk a-HPV was detected in 32 AK samples. Taken together, our findings indicate that high-risk a-HPV 16 infection could be a risk factor for the development of cSCC, suggesting a way to prevent progression to cancer. In addition, HPV 16 might induce a local immunosuppressive environment and further investigation is needed to address the mechanism.
Efficacy of ixekizumab therapy: integrated analysis of 3 double-blind, controlled trials UNCOVER-1, UNCOVER-2, UNCOVER-3 K Papp1, C Leonardi2, A Blauvelt3, N Korman4, M Ohtsuki5, K Reich6, L Mallbris7, S Ball7, J Erickson7 and CE Griffiths8 1 Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada, 2 Saint Louis University School of Medicine, St Louis, MO, 3 Oregon Medical Research Center, Portland, OR, 4 Case Western Reserve University School of Medicine, Cleveland, OH, 5 Jichi Medical University, Tochigi, Japan, 6 Dermatologikum Hamburg and Georg-August University, Hamburg, Germany, 7 Eli Lilly and Company, Indianapolis, IN and 8 University of Manchester, Manchester, United Kingdom Ixekizumab (IXE) is a high-affinity monoclonal antibody that selectively targets interleukin-17A. We present integrated efficacy data for 2 dosing regimens of IXE versus placebo (PBO) and highdose etanercept (ETN) over 12 wks to provide an overview of clinical outcomes associated with IXE treatment for psoriasis. Patients were randomized to 80 mg IXE every 2 (IXEQ2W; N¼1169) or 4 wks (IXEQ4W; N¼1165) after a 160-mg starting dose, ETN (50 mg biweekly; in 2 of 3 trials;N¼740), or PBO (N¼792). Co-primary endpoints were Wk 12 static physician global assessment (sPGA; 0: clear; 1: minimal plaque severity) and Psoriasis Area and Severity Index (PASI)75. All response rates were compared with Cochran-Mantel-Haenszel test; missing data were imputed as nonresponse. The percentage of patients with Wk 12 sPGA (0,1) was PBO 3.9%, ETN 38.9%, IXEQ4W 75.0%, and IXEQ2W 81.8%; the percentage with sPGA(0) was PBO 0.1%, ETN 7.3%, IXEQ4W 34.3%, and IXEQ2W 39.5%. The percentage of patients achieving the Wk 12 PASI75, PASI90, and PASI100 was PASI 75: PBO 4.4%, ETN 47.7%, IXEQ4W 81.6%, and IXE Q2W 88.7%; PASI 90: PBO 1.1%, ETN 22.3%, IXEQ4W 63.3%, and IXEQ2W 69.9%; and PASI100: PBO 0.1%, ETN 6.4%, IXEQ4W 33.2%, and IXEQ2W 37.6%. Both IXE groups were statistically superior to PBO (p<0.001) and ETN (p<0.001) for all comparisons. The difference in response rates for sPGA (0,1) and PASI 75 between patients treated with IXE compared with PBO was significant at Wk 1. The safety profile in the integrated analysis was comparable to that of the previously reported individual studies. Based on this analysis, response to IXE is rapid and superior to PBO and ETN.
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Ixekizumab shows no association with MACE in patients with moderate-to-severe psoriasis: an integrated safety analysis of clinical trials K Papp1, R Bissonnette2, M Ohtsuki3, L Ferris4, C Paul5, M Lebwohl6, C Leonardi7, D Braun8, F Zhao8 and K Reich9 1 K Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada, 2 Univ. of Montreal Hospital Centre, Montreal, QC, Canada, 3 Jichi Medical Univ, Tochigi, Japan, 4 Univ. of Pittsburgh, Pittsburgh, PA, 5 Toulouse Univ, Toulouse, France, 6 Mount Sinai School of Medicine, New York, NY, 7 Central Dermatology, St Louis, MO, 8 Eli Lilly and Company, Indianapolis, IN and 9 Dermatologikum Hamburg, Hamburg, Germany We assessed the incidence of major adverse cardiovascular events (MACE) in patients treated with ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin17A, vs etanercept (ETN) or placebo (PBO). Patients were randomized to IXE every 2 (IXEQ2W; N¼1167) or 4 wks (IXEQ4W; N¼1161) following a 160-mg starting dose, ETN (50 mg biweekly; N¼739), or PBO (N¼791) for 12 wks. Patients with sPGA (0,1) at Wk 12 were re-randomized to IXEQ4W (N¼416), IXEQ12W (N¼408), or PBO/IXE withdrawal (N¼402) to 60 wks. Treatmentemergent MACE were independently adjudicated; exposure-adjusted incidence rates (IRs; per 100 person-years) were calculated. At Wk 12, 0 IXEQ2W and 2 IXEQ4W patients (IR¼0.8) experienced a MACE vs 1 PBO (IR¼0.6) and 1 ETN patient (IR¼0.6); all p-values were nonsignificant (NS). In the re-randomized population, 0 IXEQ12W and 3 IXEQ4W patients (IR¼0.9) experienced a MACE vs 1 PBO/IXE withdrawal patient (IR¼0.5); all p-values were NS. Of patients exposed to IXE across the 5 Phase 3 trials, 38 experienced a MACE with IXE; exposureadjusted IR of MACE was 0.63 (CI 0.46, 0.87). At baseline, 78.9% of patients with 1 MACE had 2 preexisting cardiovascular risk factors (male 45 or female 55 yrs, diabetes mellitus, hypertension, fasting high-density lipoprotein cholesterol <40 mg/dL, and currently smoking) vs 42.1% of patients who never had a MACE; 50.0% of patients with 1 MACE were obese (30 and <40 kg/m2) vs 34.7% of patients who never had a MACE. No statistically significant difference between treatment groups in exposure-adjusted IR of MACE was observed with IXE up to Wk 60, suggesting that IXE treatment is not associated with increased risk of MACE.
S170 Journal of Investigative Dermatology (2016), Volume 136
Integrated safety of ixekizumab in patients with moderate-to-severe psoriasis: results from a pooled analysis of 7 clinical trials B Strober1, K Papp2, C Leonardi3, R Bissonnette4, L Ferris5, U Mrowietz6, C Paul7, M Lebwohl8, D Braun9 and K Reich10 1 Univ. of Connecticut, and Probity Medical Research, Farmington, CT, 2 K Papp Clinical Research and Probity Medical Research Inc, Waterloo, ON, Canada, 3 St Louis University, St Louis, MO, 4 Innovaderm Research, Montreal, QC, Canada, 5 UPMC, Pittsburgh, PA, 6 Univ. Medical Centre Schleswig-Holstein, Kiel, Germany, 7 Paul Sabatier Univ, Toulouse, France, 8 Mt Sinai School of Medicine, New York, NY, 9 Eli Lilly and Company, Indianapolis, IN and 10 Dermatologikum Hamburg and Georg-August, Gottingen, Germany We explored the safety of ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A approved for pts with psoriasis. Treatment-emergent adverse events (TEAE) and serious adverse events (SAE) were integrated from: 3 RCTs (Induction, 0-12 wks); 2 RCTs(Maintenance, 12-60 wks); and all pts exposed to IXE (7 psoriasis trials). Pts with moderate-to-severe psoriasis were randomized to IXE every 2 (IXEQ2W; N¼1167) or 4 wks (IXEQ4W; N¼1161) after a 160-mg starting dose, etanercept (ETN; 50 mg biweekly; N¼739), or placebo (PBO; N¼791) for 12 wks. At Wk 12, IXE-treated pts (sPGA 0,1) were re-randomized to IXEQ4W (N¼416), IXE every 12 wks (IXEQ12W; N¼408), or PBO/withdrawal group (N¼402). During Induction, the frequency of any TEAE was higher in Total IXE (58.6%), IXEQ2W (58.4%), IXE Q4W (58.8%), and ETN (54.0%) vs. PBO (46.8%). Most TEAEs were mild or moderate. The frequency of AEs reported as severe, SAEs, and discontinuations due to AEs did not differ among treatments. During Maintenance, the exposure-adjusted incidence rate (IReper hundred patient years) of TEAEs was lower for IXEQ4W patients than for the PBO/withdrawal group (IR: PBO, 123.8; IXEQ12W, 106.2; IXEQ4W, 95.6), with no significant difference observed between the IXEQ12W and IXEQ4W. The IR of TEAEs was lower during Maintenance than during Induction in patients who continued IXEQ4W (99.3 and 256.8, respectively). Most TEAEs were mild or moderate. IXE safety was similar to ETN, during Induction; the overall incidence of AEs in both IXE groups was similar.
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Metabolomics analysis of sweat derived from atopic dermatitis by use of nuclear magnetic resonance E Ono1, H Murota1, Y Mori2, Y Yoshioka2 and I Katamaya1 1 Dermatology, Osaka University, Suita, Japan and 2 Osaka University, Suita, Japan Sweat has been considered as a major aggravating factor of atopic dermatitis (AD). Change in the contents of sweat may involve in pathogenesis of this disease. Sweat also includes both organic components and metabolites. There has been no knowledge about the difference in organic component between healthy subjects and AD patients. Thus, comprehensive analysis of metabolites in sweat was performed by use of nuclear magnetic resonance (NMR) in this study. Healthy subjects (n¼6, age range 28-45, mean 34, all male) were employed to this study. AD (n¼13, age range 17-50, mean 34, male: female, 10: 3) patients were chosen from inpatient. Sweat was induced by sauna bathing (80degree for 10-30 min), and is collected from the subjects back. NMR device used a 5mm Bruker broadband multinuclear probe using Bruker AVANCEII 2500MHz. NMR spectrum of the back sweat derived from healthy subjects were characterized by intense signals of lactate, pyruvate, and glycerol. Peak in glucose and hippuric acid were found specifically in sweat derived from subjects with AD. Sweat glucose concentration was measured by ELISA, and was divided into a low and a high glucose group. When comparing these two groups, SCORAD score tended to be high in high level of glucose group. Furthermore, glucose concentration were significantly correlated with SCORAD score (p¼0.0003). To clarify the mechanism of high glucose concentration in AD sweat, immunohistological analysis for glucose transporter such as GLUT or SGLT, which is known to play a substantial role in kidney, was performed, and we found GLUT2 expressed in the human sweat gland. Moreover, GLUT2 located in cytoplasm of secretory cells with appearance of granule in non-AD skin. On the other hand, in AD skin, GLUT2 located on the lumen of secretory cells. From these results, glucose in sweat might be a biomarker for severity of AD.
Impact of ixekizumab on palmoplantar plaque psoriasis compared to placebo and etanercept: results from UNCOVER 2 A Menter1, K Reich2, RB Warren3, KC Duffin4, R Langley5, L Kerr6, E Dennehy6, DS Shrom6 and D Amato6 1 University of Texas Southwestern Medical Center, Dallas, TX, 2 Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany, 3 University of Manchester, Salford, United Kingdom, 4 University of Utah, Sal Lake City, UT, 5 Dalhousie University, Halifax, NS, Canada and 6 Eli Lilly and Company, Indianapolis, IN Ixekizumab (IXE) is a high-affinity monoclonal antibody that selectively targets interleukin17A. In this analysis, the efficacy of IXE for psoriasis patients with moderate-to-severe palmoplantar involvement versus etanercept (ETN) and placebo (PBO) was evaluated. In the UNCOVER 2 trial, patients were randomized to PBO (N¼168), ETN (50 mg twice weekly; N¼358), or a single injection of 80 mg IXE every 2 weeks (IXE Q2W; N¼351) or every 4 weeks (IXE Q4W; N¼347) following a 160-mg starting dose at Week 0. Psoriatic involvement on hands and feet was assessed with the Palmoplantar Psoriasis Area and Severity Index (PPASI) (severity score range: 0 to 72). The percentage of patients with 100% reduction from baseline on the PPASI was analyzed in patients with baseline scores >¼8 (moderate-to-severe palmoplantar involvement). Treatment groups were compared using Cochran-MantelHaenszel test; missing data were imputed using non-responder imputation. At baseline, the percentage of patients with palmoplantar psoriasis in each treatment group was PBO, 32.7%; ETN, 26.5%; IXE Q2W, 29.6%; and IXE Q4W, 29.4%. Of those patients with PPASI scores >¼8 (n¼105), the overall mean (SD) baseline score was 19.4 (12.3). At 12 weeks, the percentage of patients within this population who had achieved 100% reduction in the PPASI score was statistically significantly greater with IXE Q2W (51.6% [n¼16 of 31], p<.001) and IXE Q4W (45.5% [n¼10 of 22], p¼.031) compared to PBO (5.6% [n¼1 of 18]). In addition, IXE Q2W showed superiority over ETN (29.4% [n¼10 of 34], p¼.039). There were no unexpected safety findings for patients treated with IXE. At Week 12, IXE was superior to PBO, and IXE Q2W was superior to ETN for 100% improvement in patients with moderate-tosevere palmoplantar plaque psoriasis.
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Detection of high-risk human papillomavirus DNA in cutaneous squamous cell carcinoma among young patients R Aoki, B Clanner-Engelshofen, B Feldner, L Birrou, T Ruzicka and M Reinholz Dermatology and Allergy, Ludwig-Maximilian-University, Munich, Germany High-risk mucosal a-Human papillomaviruses (a-HPV) are linked to cervical, anogenital and oropharyngeal cancers. Persistent infection with high-risk a-HPV can cause epithelial hyperplasia, leading to the development of squamous cell carcinoma. Additionally, cutaneous b-HPV are strongly associated with cutaneous squamous cell carcinoma (cSCC) in a specific group of patients and many recent studies have focused on the etiological role of b-HPV for cSCC and actinic keratosis (AK). However, the correlation between high-risk a-HPV and cSCC remains to be well defined, with previous reports showing conflicting results. In order to evaluate the possibility of high-risk a-HPV etiology for cSCC and AK, we compared HPV infections in cutaneous lesions obtained from young (under 60) or elderly (over 60) cSCC, AK patients and matched population controls. HPV detection was performed using polymerase chain reaction (PCR) in skin biopsies (24 young cSCC, 20 elderly cSCC, 32 AK and 10 normal young skins) and the DNA samples were used for HPV typing with DNA chip assay. Sixteen out of 24 (67%) skin lesions in young cSCC patients were found to be positive for high-risk a-HPV DNA and HPV type 16 were present in 94% of high-risk a-HPVpositive patients. HPV16 incidence was eight of 20 (40%) in elderly cSCC and one of 10 (10%) in the young normal skins. The higher prevalence of HPV16 in young cSCC patients suggests an association of HPV16 with cSCC especially among young population. High-risk a-HPV were detected more frequently in young cSCC samples from sun-exposed compared with non-exposed areas, implicating UV radiation as a possible risk factor for HPV detection. However, none of high-risk a-HPV was detected in 32 AK samples. Taken together, our findings indicate that high-risk a-HPV 16 infection could be a risk factor for the development of cSCC, suggesting a way to prevent progression to cancer. In addition, HPV 16 might induce a local immunosuppressive environment and further investigation is needed to address the mechanism.
Efficacy of ixekizumab therapy: integrated analysis of 3 double-blind, controlled trials UNCOVER-1, UNCOVER-2, UNCOVER-3 K Papp1, C Leonardi2, A Blauvelt3, N Korman4, M Ohtsuki5, K Reich6, L Mallbris7, S Ball7, J Erickson7 and CE Griffiths8 1 Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada, 2 Saint Louis University School of Medicine, St Louis, MO, 3 Oregon Medical Research Center, Portland, OR, 4 Case Western Reserve University School of Medicine, Cleveland, OH, 5 Jichi Medical University, Tochigi, Japan, 6 Dermatologikum Hamburg and Georg-August University, Hamburg, Germany, 7 Eli Lilly and Company, Indianapolis, IN and 8 University of Manchester, Manchester, United Kingdom Ixekizumab (IXE) is a high-affinity monoclonal antibody that selectively targets interleukin-17A. We present integrated efficacy data for 2 dosing regimens of IXE versus placebo (PBO) and highdose etanercept (ETN) over 12 wks to provide an overview of clinical outcomes associated with IXE treatment for psoriasis. Patients were randomized to 80 mg IXE every 2 (IXEQ2W; N¼1169) or 4 wks (IXEQ4W; N¼1165) after a 160-mg starting dose, ETN (50 mg biweekly; in 2 of 3 trials;N¼740), or PBO (N¼792). Co-primary endpoints were Wk 12 static physician global assessment (sPGA; 0: clear; 1: minimal plaque severity) and Psoriasis Area and Severity Index (PASI)75. All response rates were compared with Cochran-Mantel-Haenszel test; missing data were imputed as nonresponse. The percentage of patients with Wk 12 sPGA (0,1) was PBO 3.9%, ETN 38.9%, IXEQ4W 75.0%, and IXEQ2W 81.8%; the percentage with sPGA(0) was PBO 0.1%, ETN 7.3%, IXEQ4W 34.3%, and IXEQ2W 39.5%. The percentage of patients achieving the Wk 12 PASI75, PASI90, and PASI100 was PASI 75: PBO 4.4%, ETN 47.7%, IXEQ4W 81.6%, and IXE Q2W 88.7%; PASI 90: PBO 1.1%, ETN 22.3%, IXEQ4W 63.3%, and IXEQ2W 69.9%; and PASI100: PBO 0.1%, ETN 6.4%, IXEQ4W 33.2%, and IXEQ2W 37.6%. Both IXE groups were statistically superior to PBO (p<0.001) and ETN (p<0.001) for all comparisons. The difference in response rates for sPGA (0,1) and PASI 75 between patients treated with IXE compared with PBO was significant at Wk 1. The safety profile in the integrated analysis was comparable to that of the previously reported individual studies. Based on this analysis, response to IXE is rapid and superior to PBO and ETN.
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Ixekizumab shows no association with MACE in patients with moderate-to-severe psoriasis: an integrated safety analysis of clinical trials K Papp1, R Bissonnette2, M Ohtsuki3, L Ferris4, C Paul5, M Lebwohl6, C Leonardi7, D Braun8, F Zhao8 and K Reich9 1 K Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada, 2 Univ. of Montreal Hospital Centre, Montreal, QC, Canada, 3 Jichi Medical Univ, Tochigi, Japan, 4 Univ. of Pittsburgh, Pittsburgh, PA, 5 Toulouse Univ, Toulouse, France, 6 Mount Sinai School of Medicine, New York, NY, 7 Central Dermatology, St Louis, MO, 8 Eli Lilly and Company, Indianapolis, IN and 9 Dermatologikum Hamburg, Hamburg, Germany We assessed the incidence of major adverse cardiovascular events (MACE) in patients treated with ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin17A, vs etanercept (ETN) or placebo (PBO). Patients were randomized to IXE every 2 (IXEQ2W; N¼1167) or 4 wks (IXEQ4W; N¼1161) following a 160-mg starting dose, ETN (50 mg biweekly; N¼739), or PBO (N¼791) for 12 wks. Patients with sPGA (0,1) at Wk 12 were re-randomized to IXEQ4W (N¼416), IXEQ12W (N¼408), or PBO/IXE withdrawal (N¼402) to 60 wks. Treatmentemergent MACE were independently adjudicated; exposure-adjusted incidence rates (IRs; per 100 person-years) were calculated. At Wk 12, 0 IXEQ2W and 2 IXEQ4W patients (IR¼0.8) experienced a MACE vs 1 PBO (IR¼0.6) and 1 ETN patient (IR¼0.6); all p-values were nonsignificant (NS). In the re-randomized population, 0 IXEQ12W and 3 IXEQ4W patients (IR¼0.9) experienced a MACE vs 1 PBO/IXE withdrawal patient (IR¼0.5); all p-values were NS. Of patients exposed to IXE across the 5 Phase 3 trials, 38 experienced a MACE with IXE; exposureadjusted IR of MACE was 0.63 (CI 0.46, 0.87). At baseline, 78.9% of patients with 1 MACE had 2 preexisting cardiovascular risk factors (male 45 or female 55 yrs, diabetes mellitus, hypertension, fasting high-density lipoprotein cholesterol <40 mg/dL, and currently smoking) vs 42.1% of patients who never had a MACE; 50.0% of patients with 1 MACE were obese (30 and <40 kg/m2) vs 34.7% of patients who never had a MACE. No statistically significant difference between treatment groups in exposure-adjusted IR of MACE was observed with IXE up to Wk 60, suggesting that IXE treatment is not associated with increased risk of MACE.
S170 Journal of Investigative Dermatology (2016), Volume 136
Integrated safety of ixekizumab in patients with moderate-to-severe psoriasis: results from a pooled analysis of 7 clinical trials B Strober1, K Papp2, C Leonardi3, R Bissonnette4, L Ferris5, U Mrowietz6, C Paul7, M Lebwohl8, D Braun9 and K Reich10 1 Univ. of Connecticut, and Probity Medical Research, Farmington, CT, 2 K Papp Clinical Research and Probity Medical Research Inc, Waterloo, ON, Canada, 3 St Louis University, St Louis, MO, 4 Innovaderm Research, Montreal, QC, Canada, 5 UPMC, Pittsburgh, PA, 6 Univ. Medical Centre Schleswig-Holstein, Kiel, Germany, 7 Paul Sabatier Univ, Toulouse, France, 8 Mt Sinai School of Medicine, New York, NY, 9 Eli Lilly and Company, Indianapolis, IN and 10 Dermatologikum Hamburg and Georg-August, Gottingen, Germany We explored the safety of ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A approved for pts with psoriasis. Treatment-emergent adverse events (TEAE) and serious adverse events (SAE) were integrated from: 3 RCTs (Induction, 0-12 wks); 2 RCTs(Maintenance, 12-60 wks); and all pts exposed to IXE (7 psoriasis trials). Pts with moderate-to-severe psoriasis were randomized to IXE every 2 (IXEQ2W; N¼1167) or 4 wks (IXEQ4W; N¼1161) after a 160-mg starting dose, etanercept (ETN; 50 mg biweekly; N¼739), or placebo (PBO; N¼791) for 12 wks. At Wk 12, IXE-treated pts (sPGA 0,1) were re-randomized to IXEQ4W (N¼416), IXE every 12 wks (IXEQ12W; N¼408), or PBO/withdrawal group (N¼402). During Induction, the frequency of any TEAE was higher in Total IXE (58.6%), IXEQ2W (58.4%), IXE Q4W (58.8%), and ETN (54.0%) vs. PBO (46.8%). Most TEAEs were mild or moderate. The frequency of AEs reported as severe, SAEs, and discontinuations due to AEs did not differ among treatments. During Maintenance, the exposure-adjusted incidence rate (IReper hundred patient years) of TEAEs was lower for IXEQ4W patients than for the PBO/withdrawal group (IR: PBO, 123.8; IXEQ12W, 106.2; IXEQ4W, 95.6), with no significant difference observed between the IXEQ12W and IXEQ4W. The IR of TEAEs was lower during Maintenance than during Induction in patients who continued IXEQ4W (99.3 and 256.8, respectively). Most TEAEs were mild or moderate. IXE safety was similar to ETN, during Induction; the overall incidence of AEs in both IXE groups was similar.