Cutaneous tolerability of a novel topical minocycline gel for the treatment of rosacea

Cutaneous tolerability of a novel topical minocycline gel for the treatment of rosacea

Presenters: Bhatia N1, Ahmadyar M1, Hansra H2, Del Rosso J3, Baldwin H4, Daniels AM5

Affiliations: 1Therapeutics Clinical Research, San Diego, CA; 2BioPharmX, Inc., Menlo Park, CA; 3JDR Dermatology Research, LLC, Las Vegas, NV; 4The Acne Treatment and Research Center, Morristown, NJ

Background/Objective: Rosacea is a chronic and relapsing skin disorder that primarily involves the central face. Affecting at least 16 million people in the United States alone, rosacea can develop via genetic, immunologic, inflammatory, vascular, or environmental pathways. The papulopustular subtype resembles acne vulgaris in its formation of inflammatory papules, pustules, and plaques.

Minocycline is effective as a first-line systemic therapy for rosacea. It is thought that, like other tetracyclines, its anti-inflammatory properties are responsible. Unfortunately, oral and/or long-term use, as required in a chronic condition such as rosacea, might contribute to antibiotic resistance. Additionally, significant side effects such as gastrointestinal distress and vertigo might make oral minocycline intolerable. Therefore, another form of delivery is needed.

Methods: This was a Phase II feasibility study of 1% and 2% formulations of a novel topical minocycline gel. Nineteen adults with moderate-to-severe papulopustular rosacea participated. Skin diseases, prohibited comorbidities and treatments, and pregnancy were exclusionary.

Treatment was open-label and nonrandomized. Subjects applied the assigned gel to the face once per day for 12 weeks. Numbers of facial lesions and their severity were assessed throughout the study. Safety endpoints were also recorded, as were ratings of the cutaneous tolerability (4-point severity scales, investigator- and subject-reported).

Results: The treatment was well tolerated. According to ratings for erythema, scaling/peeling, and edema, none of the subjects experienced worsening of rosacea. Ratings for burning, stinging, tightness, and itching showed that the majority of the subjects improved or were unchanged. Only a single subject reported severe cutaneous irritation at Week 12 (burning, stinging, and itching). Additionally, there were no study-related adverse events or clinically significant changes in laboratory values. Additionally, for both formulations, lesion count and severity were reduced with rapid onset. Clinically meaningful improvements were reported after just four weeks of treatment. The majority of subjects stated they would use the minocycline gel again.

Conclusion: Both formulations of the novel topical minocycline gel demonstrated improvement in treating rosacea and had good cutaneous tolerability profiles. Because cutaneous symptoms such as erythema, edema, burning, and stinging are commonly reported symptoms of rosacea itself, it is to be expected that these were reported with some frequency at baseline. Improvements, which were observed for the majority of subjects in most measures, might therefore be indicative of an improvement in the underlying condition as well as a lack of treatment reaction. Additionally, safety endpoints were met and there was evidence for the effectiveness of treatment in the rapid reduction in number and severity of facial lesions. Although generalizability is limited by the study’s small size and open-label, single-center design, this new therapy shows promise as a new treatment option for rosacea. An important advantage of the topical minocycline formulation might be in reduction of risks associated with systemic exposure to this antibiotic. Next-phase clinical studies are planned.

Secukinumab achievement of psoriatic arthritis disease activity score- (PASDAS) related remission: two-year results from a Phase III study

Secukinumab achievement of psoriatic arthritis disease activity score- (PASDAS) related remission: two-year results from a Phase III study

Presenters: Coates LC1, Gladman DD2, Nash P3, Fitzgerald O4, Kavanaugh A5, Rasouliyan L6, Pricop L7, Ding K7, Gaillez C8 (on behalf of the FUTURE 2 Study Group)

Affiliations: 1Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; 2Toronto Western Hospital, Toronto, ON, Canada; 3University of Queensland, Brisbane, Australia; 4St. Vincent’s University Hospital, Dublin, Ireland; 5UC San Diego School of Medicine, La Jolla, CA; 6RTI Health Solutions, Barcelona, Spain; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ; 8Novartis Pharma AG, Basel, Switzerland.

Background/Objective: Psoriatic Arthritis Disease Activity Score (PASDAS) assessing multiple facets of psoriatic arthritis (PsA) has been shown to distinguish treatment effect and perform better in statistical terms than traditional joint-only indices and could be used as a treatment target in clinical trials in PsA. Secukinumab significantly improved the signs and symptoms of PsA over 104 weeks in the FUTURE 2 study. This post-hoc analysis assessed the ability of secukinumab to achieve low disease activity (LDA) or remission (REM) using PASDAS through 104 weeks in the FUTURE 2 study.

Methods: The FUTURE 2 study design was previously published. PASDAS index is derived from Physician’s Global Visual Analog Scale, patient’s global VAS, SF-36 PCS, tender and swollen joint counts, Leeds enthesitis count, dactylitis count and c-reactive protein level with validated cut-points for high disease activity (HDA ?5.4), moderate disease activity (3.2< MoDA <5.4), 1.9<LDA ?3.2 and REM ?1.9.3

Results: PASDAS scores at baseline was similar across the three treatment groups. In the overall population at Week 16, PASDAS REM, LDA, and MoDA were achieved in 15.6 percent, 22.9 percent, and 49.0 percent, respectively, of patients treated with secukinumab 300 mg; of patients treated with secukinumab 150mg, 15.2 percent, 19.2 percent, and 42.4 percent, respectively; and of patients given placebo, 2.3 percent, 13.8 percent, and 44.8 percent, respectively. At Week 104, REM was achieved in 22.9 percent and 14.3 percent of patients treated with secukinumab 300mg and 150mg, respectively. In anti–TNF-naïve patients at Week 16, PASDAS REM, LDA, and MoDA were achieved in 18.5 percent, 27.7 percent, and 46.2 percent, respectively, of patients treated with secukinumab 300mg; of patients treated with secukinumab 150mg, 22.2 percent, 20.6 percent, and 42.9 percent, respectively; and of patients given placebo, 3.5 percent, 14.0 percent, and 45.6 percent, respectively. At Week 104 in anti–TNF-naïve patients, REM was achieved in 29.1 percent and 17.0 percent of patients treated with secukinumab 300mg and 150mg, respectively. In anti–TNF-inadequate response (IR) patients at Week 16, PASDAS REM, LDA, and MoDA were achieved in 9.7 percent, 12.9 percent, and 54.8 percent, respectively, of patients treated with secukinumab 300mg; of patients treated with secukinumab 150mg, 2.8 percent, 16.7 percent, and 41.7 percent, respectively; of patients given placebo, 0 percent, 13.3 percent, and 43.3 percent, respectively. At Week 104 in anti–TNF-IR patients, REM was achieved in 10.7 percent and 8.3 percent of patients treated with secukinumab 300mg and 150mg, respectively. The proportion of patients achieving PASDAS REM/LDA at Weeks 16 and 104 was similar, irrespective of time since first diagnosis, for both secukinumab doses. Secukinumab treated patients achieving PASDAS REM had significantly greater improvements in function, physical- and mental-health quality of life, and fatigue compared to HDA through Week 104.

Conclusion: At Week 16, PASDAS REM and LDA were achieved in 38.5 percent and 34.4 percent of patients treated with secukinumab 300mg and 150mg, respectively, versus 16.1 percent in the placebo group, with approximately 50 percent of patients achieving PASDAS REM and LDA in both secukinumab groups at Week 104. A higher proportion of anti–TNF-naïve patients treated with secukinumab achieved PASDAS REM or LDA than those treated with anti–TNF-IR through Week 104. Secukinumab treated patients achieving PASDAS REM had significantly greater improvements in function, quality of life, and fatigue.

Funding: This research was sponsored by Novartis Pharma AG in Basel, Switzerland.

Radiographic progression of structural joint damage in patients with active psoriatic arthritis treated with ixekizumab over 52 weeks

Radiographic progression of structural joint damage in patients with active psoriatic arthritis treated with ixekizumab over 52 weeks

Presenters: van der Heijde D1, Okada M2, Lee C3, Shuler CL3, Rathmann S3, Amato D3, Lin CY3, and Mease P4

Affiliations: 1Leiden University Medical Centre, Leiden, the Netherlands; 2St. Luke’s International Hospital, Tokyo, Japan; 3Eli Lilly and Company, Indianapolis, IN; 4Swedish Medical Center and University of Washington, Seattle, WA

Background/Objective: Ixekizumab (IXE), an anti-interleukin-17A monoclonal antibody, was shown to be superior to placebo (PBO) in clinical responses and in inhibition of the progression of structural joint damage in patients with psoriatic arthritis (PsA) treated for 24 weeks. Here, we assessed progression of structural joint damage in PsA patients with IXE for up to 52 weeks.

Methods: Biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with active PsA (n=417) entered into SPIRIT-P1 (NCT01695239), a double-blind Phase III trial. Patients must have had at least one joint erosion on the hand and foot confirmed by central x-ray reading or have had a C-reactive protein level less than 6mg/L at screening. A total of 417 patients were randomized to IXE 80mg every two (Q2W; n=103) or four weeks (Q4W; n=107) following a 160mg initial dose, PBO (n=106), or adalimumab 40mg every two weeks (ADA; active reference arm; n=101) for 24 weeks. In the Extension Period (EXT; Weeks 24–52), patients on PBO and ADA were re-randomized (1:1) to IXEQ2W or IXEQ4W at Week 16 (inadequate responders) or Week 24; patients on ADA underwent a washout prior to IXE treatment. All patients were assessed for structural joint damage using the van der Heijde modified PsA Total Sharp Score (mTSS, 0–528 scale). Two readers blinded to timepoint scored X-rays at Weeks 0, 24, and 52 independently and clinical data (average of readers). The mTSS was excluded from the prespecified analysis if the radiograph was taken after the scheduled visit date. In a post-hoc analysis, mTSS from a radiograph taken after the scheduled visit date was interpolated and considered as observed data. Any missing data at Week 52, in either presentation, were imputed using a linear extrapolation if they had at least one post-baseline value.

Results: Of the patients who had active PsA at Week 0, 381 patients (91.3%) entered the EXT, with 374 (98.2%) having radiographs collected during the EXT. Week 52 mean (SD) mTSS change from baseline were 0.54 (2.11) and 0.09 (1.0) for patients randomized to IXEQ4W and IXEQ2W at baseline, respectively. Similarly, post-hoc analysis changes at Week 52 were 0.47 (1.9) and 0.09 (0.9) for the IXEQ4W and IXEQ2W groups, respectively. The majority of patients on IXEQ2W or IXEQ4W exhibited no structural progression through one year of IXE treatment. In patients who switched from PBO or ADA to IXE, the Week 52 mean change from baseline mTSS values scores ranged from -0.03 to 0.41.

Conclusion: Over a 52-week period, minimal changes in mTSS were observed in patients with PsA entering the EXT and treated with IXEQ2W or IXEQ4W.

Secukinumab for the treatment of scalp, nail, and palmoplantar psoriasis

Secukinumab for the treatment of scalp, nail, and palmoplantar psoriasis

Presenters: Hawkes JE1,2, Lebwohl M2, Elewski B3, Kircik L2,4, Reich K5, Muscianisi E6, Gottlieb A7

Affiliations: 1The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3University of Alabama, Birmingham, AL; 4Indiana University School of Medicine, Indianapolis, IN; 5Dermatologikum Hamburg, Hamburg, Germany; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ 7New York Medical College, Valhalla, NY

Background/Objective: Psoriasis is a chronic, immune-mediated, systemic condition that commonly affects the scalp, nails, palms, and soles. Although psoriasis in these areas accounts for a small percentage of total body surface area, it often results in significant dysfunction and quality of life impairment. For instance, the highly visible nature of scalp psoriasis can cause embarrassment and discomfort. Psoriatic nail disease is often overlooked, causing cosmetic concerns and difficulty with tasks requiring manual dexterity. Palmoplantar psoriasis causes significant functional impairment compared with other psoriasis subtypes and can be recalcitrant to traditional systemic therapies. Until recently, there has been limited clinical research focused on less common and hard-to-treat subtypes or clinical features of psoriatic disease. Secukinumab, a human monoclonal antibody that selectively binds to and neutralizes interleukin-17A, has demonstrated efficacy for chronic plaque psoriasis in a structured Phase III development plan. Here we present a review of the efficacy and safety of secukinumab in patients with psoriasis affecting the scalp, nails, palms, and soles of the feet.

Methods: In three separate clinical trials designed specifically for each of these hard-to-treat areas, inclusion criteria included patients with moderate-to-severe scalp psoriasis (Psoriasis Scalp Severity Index [PSSI] ?12), patients with moderate-to-severe psoriasis with significant nail involvement (Nail Psoriasis Severity Index [NAPSI] ?16 with ?4 fingernails involved), and patients with moderate-to-severe palmoplantar psoriasis (palmoplantar Investigator’s Global Assessment [ppIGA] ?3), respectively. In all trials, patients received secukinumab 300mg or 150mg at baseline, Weeks 1, 2 and 3, and then every four weeks beginning at Week 4.

Results: The primary endpoint of each trial was met. In 102 patients with scalp psoriasis, PSSI 90-percent improvement response rates were significantly greater with secukinumab 300mg versus placebo at Week 12 (52.9% vs. 2.0%; P<0.001). One in 198 patients with nail psoriasis, mean NAPSI percent change from baseline to Week 16 was significantly greater in secukinumab 300mg (-45.3%) and secukinumab 150mg (-37.9%) groups compared to placebo (-10.8%; both P<0.0001). In 205 patients with nonpustular palmoplantar psoriasis, ppIGA0/1 was achieved at Week 16 by significantly more patients with secukinumab 300mg (33.3%) and secukinumab 150mg (22.1%) than with placebo (1.5%; both P<0.001). The safety of secukinumab in these trials was consistent with the safety profile observed in previous clinical trials, and no new safety signals were identified.

Conclusion: Secukinumab is a safe and effective treatment option in chronic plaque psoriasis and these hard-to-treat psoriasis subtypes as demonstrated in specifically designed prospective clinical trials.

Funding: This research was sponsored by Novartis Pharma AG, Basel, Switzerland, and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

Secukinumab is superior to ustekinumab in clearing skin of patients with moderate-to-severe plaque psoriasis: CLARITY, a randomized, controlled, Phase IIIb trial

Secukinumab is superior to ustekinumab in clearing skin of patients with moderate-to-severe plaque psoriasis: CLARITY, a randomized, controlled, Phase IIIb trial

Presenters: Bagel J1, Nia J2, Hashim P2, Patekar M3, de Vera A3, Hugot S3, Sheng K4, Xia S5, Muscianisi E4, Blauvelt A6, Lebwohl M2

Affiliations: 1Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ; 5Novartis Beijing Novartis Pharma Co. Ltd, Shanghai, China; 6Oregon Medical Research Center, Portland, OR

Background/Objective: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has previously demonstrated superior efficacy to ustekinumab in the Phase IIIb CLEAR study of moderate-to-severe plaque psoriasis. Here, we report 16-week results from CLARITY, the second head-to-head trial comparing secukinumab with ustekinumab.

Methods: In this ongoing multicenter, head-to-head, double-blind, parallel-group, Phase IIIb study (NCT02826603), patients were randomized 1:1 to receive subcutaneous secukinumab 300mg or ustekinumab per label. The co-primary objectives were to demonstrate the superiority of secukinumab over ustekinumab at Week 12 in relation to the proportion of patients with 1) 90-percent or more improvement from baseline Psoriasis Area and Severity Index (PASI 90) and 2) a score of 0/1 (clear/almost clear) on the Investigator’s Global Assessment (IGA mod 2011 0/1). Key secondary objectives included demonstrating the superiority of secukinumab over ustekinumab with respect to PASI 75 at Week 4; PASI 75 and 100 at Week 12; PASI 75, 90, 100; and IGA mod 2011 0/1 at Week 16. Missing values were handled by multiple imputation.

Results: At Week 12, both co-primary objectives were met, secukinumab 300 mg (n=550) was significantly superior to ustekinumab (n=552) for the proportion of patients achieving both PASI 90 (66.5% vs. 47.9%; P<0.0001) and IGA mod 2011 0/1 (72.3% vs 55.4%; P<0.0001) response rates. Additionally, all key secondary objectives were met. At Week 4, PASI 75 response rates were significantly superior with secukinumab 300mg compared to ustekinumab (40.2% vs 16.3%; P<0.0001). At Week 16, secukinumab 300mg demonstrated significantly superior response rates compared to ustekinumab for PASI 75 (91.7% vs. 79.8%; P<0.0001), PASI 90 (76.6% vs. 54.2%; P<0.0001), PASI 100 (45.3% vs. 26.7%; P<0.0001), and IGA mod 2011 0/1 (78.6% vs. 59.1%; P<0.0001). Furthermore, at Week 12, patients receiving secukinumab 300mg compared to ustekinumab had significantly greater PASI 75 (88.0% vs. 74.2%; P<0.0001) and PASI 100 (38.1% vs. 20.1%; P<0.0001) responses. Safety findings were consistent with the known safety profile of secukinumab.

Conclusion: Secukinumab demonstrated superior results with greater improvements compared to ustekinumab across all study outcomes at Weeks 4, 12, and 16 in patients with moderate-to-severe plaque psoriasis.

Funding: This research was sponsored by Novartis Pharma AG, Basel, Switzerland.

Efficacy of brodalumab in ustekinumab-naive and -experienced patients with moderate-to-severe plaque psoriasis

Efficacy of brodalumab in ustekinumab-naive and -experienced patients with moderate-to-severe plaque psoriasis

Presenters: Hsu S1, Green L2, Keegan BR3, Kircik L4, Rastogi S5, Pillai R6, Israel RJ5

Affiliations: 1Temple University School of Medicine, Philadelphia, PA; 2George Washington University School of Medicine, Washington, DC; 3Psoriasis Treatment Center of Central New Jersey/Windsor Dermatology, East Windsor, NJ; 4Icahn School of Medicine at Mount Sinai, New York, NY; 5Valeant Pharmaceuticals North America LLC, Bridgewater, NJ; 6Dow Pharmaceutical Sciences, Petaluma, CA

Background/Objective: Brodalumab is a fully human anti–interleukin-17 receptor A (IL-17RA) monoclonal antibody that has shown efficacy in patients with moderate-to-severe plaque psoriasis. We evaluated the efficacy of brodalumab in a post-hoc analysis of a subset of patients with prior exposure to ustekinumab, a human anti-IL-12 and -IL-23 monoclonal antibody approved for the treatment of moderate-to-severe plaque psoriasis who were enrolled in a Phase III, multicenter, randomized, double-blind, placebo-controlled study (AMAGINE-1).

Methods: During the induction phase, patients received brodalumab 210mg weekly for the first three weeks and every two weeks (Q2W) thereafter for 12 weeks. After 12 weeks, patients who achieved a static physician’s global assessment (sPGA) score of 0 or 1 continued to the withdrawal phase and were rerandomized 1:1 to receive brodalumab 210mg Q2W or placebo for up to 52 weeks. Beginning at Week 16, all rerandomized patients who experienced return of disease (sPGA ?3) qualified for retreatment with their induction dose of brodalumab 210mg and were imputed as nonresponders at the time of qualification. Skin clearance was monitored by the Psoriasis Area and Severity Index (PASI) and the sPGA.

Results: Of 167 patients who were randomized to brodalumab 210mg in the induction phase and continued into the withdrawal phase, 19.2 percent had taken ustekinumab prior to the start of the trial (n=32). Among patients receiving continuous brodalumab 210mg, rates of 100-percent reduction in PASI score (PASI 100) were 65.2 percent (n=43/66) and 76.5 percent (n=13/17) in ustekinumab-naive and -experienced patients, respectively (rates for placebo were 0 [n=0/69] and 0 [n=0/15], respectively). Similarly, rates of PASI 75 and PASI 90 were 84.8 percent (n=56/66) and 75.8 percent (n=50/66), respectively, in ustekinumab-naive patients and 94.1 percent (n=16/17) and 88.2 percent (n=15/17), respectively, in ustekinumab-experienced patients (rates for placebo were 0 [n=0 of 69] and 0 [n=0 of 69], respectively, in ustekinumab-naive patients and 0 [n=0/15] and 0 [n=0/15], respectively, in ustekinumab-experienced patients).

Conclusion: Brodalumab 210mg was associated with improved skin clearance efficacy in both patients with and without prior ustekinumab exposure.

Funding: This study was sponsored by Amgen Inc.

Long-term efficacy of brodalumab for the treatment of moderate-to-severe psoriasis: data from a pivotal Phase III clinical trial

Long-term efficacy of brodalumab for the treatment of moderate-to-severe psoriasis: data from a pivotal Phase III clinical trial

Presenters: Menter A1, Sobell J2, Silverberg JI3, Lebwohl M4, Rastogi S5, Pillai R6, Israel RJ5

Affiliations: 1Baylor University Medical Center, Dallas, TX; 2SkinCare Physicians, Chestnut Hill, MA; 3Northwestern University Feinberg School of Medicine, Chicago, IL; 4Icahn School of Medicine at Mount Sinai, New York, NY; 5Valeant Pharmaceuticals North America LLC, Bridgewater, NJ; 6Dow Pharmaceutical Sciences, Petaluma, CA

Background/Objective: Brodalumab is a fully human anti-interleukin-17 receptor A (IL-17RA) monoclonal antibody that antagonizes the action of specific inflammatory cytokines involved in psoriasis. Pivotal Phase III clinical trials demonstrated the efficacy and safety of brodalumab through 52 weeks of treatment in patients with moderate-to-severe psoriasis. We evaluated the efficacy of brodalumab in psoriasis from Week 52 through Week 120. Data were derived from the long-term, open-label extension study of a 52-week, randomized, double-blind, placebo- and active comparator-controlled clinical trial (AMAGINE-2).

Methods: Patients received brodalumab 210mg or 140mg every two weeks (Q2W), ustekinumab, or placebo during a 12-week induction phase, followed by a maintenance phase through Week 52. During the maintenance phase, patients receiving brodalumab were rerandomized to a different dose and interval of brodalumab (210mg or 140mg Q2W, Q4W, or Q8W), patients receiving placebo were switched to brodalumab 210mg Q2W, and patients receiving ustekinumab continued on ustekinumab. At Week 52, patients who received brodalumab during the maintenance phase continued receiving their maintenance dose of brodalumab, and patients who were taking ustekinumab switched to brodalumab 210mg Q2W. Data are presented for patients who received brodalumab 210mg Q2W (the FDA-approved dose) through Week 120 of the long-term extension phase.

Results: A total of 1,392 patients received brodalumab 210mg Q2W in the long-term extension phase. At Week 52, rates (95% confidence interval [CI]) of these patients for Psoriasis Area and Severity Index (PASI) 75-percent improvement (PASI 75), PASI 90, and PASI 100 were 90.6 percent (88.9%-92.2%), 77.6 percent (75.2%-79.9%), and 53.3 percent (50.5%-56.0%), respectively. Similarly, at Week 120, corresponding responder rates (95% CI) were 88.4 percent (86.0%-90.6%), 76.8 percent (73.6%-79.7%), and 56.2 percent (52.7%-59.7%), respectively. Success rates (95% CI), based on static physician’s global assessment score of 0 or 1, were 79.2 percent (76.8%-81.4%) and 76.6 percent (73.5%-79.6%) at Weeks 52 and 120, respectively. The patients who received continuous brodalumab 210mg Q2W (n=334) achieved Static Physician’s Global Assessment Score of 0 or 1, PASI 75, PASI 90, and PASI 100 response of 79.2, 86.5, 76.4, and 59.0 percent, respectively, through Week 120.

Conclusion: Treatment with brodalumab resulted in substantial psoriatic lesion clearing for more than two years in most patients with moderate-to-severe psoriasis.

Funding: This study was sponsored by Amgen Inc.

Incidence of inflammatory bowel disease in patients treated with secukinumab: pooled analysis of 21 randomized controlled Phase III and IV clinical trials of psoriasis, psoriatic arthritis, and ankylosing spondylitis

Incidence of inflammatory bowel disease in patients treated with secukinumab: pooled analysis of 21 randomized controlled Phase III and IV clinical trials of psoriasis, psoriatic arthritis, and ankylosing spondylitis

Presenters: Schreiber S1, Colombel JF2, Feagan BG3, Blauvelt A4, Reich K5, Deodhar A6, McInnes IB7, Porter B8, Gupta AD9, Pricop L8, Fox T10

Affiliations: 1Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany; Institute of Clinical Molecular Biology, University of Kiel, Germany; 2Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York; 3University of Western Ontario, Ontario, Canada; 4Oregon Medical Research Center, Portland, Oregon; 5Dermatologikum Hamburg and Georg-August-University, Göttingen, Germany; 6Oregon Health & Science University, Portland, OR; 7Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK; 8Novartis Pharmaceuticals Corporation, East Hanover, NJ; 9Novartis Healthcare Pvt. Ltd., Hyderabad, India; 10Novartis Pharma AG, Basel, Switzerland

Background/Objective: Inflammatory bowel disease (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are common comorbidities associated with psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Compared to the general population, epidemiological studies have shown that patients with psoriasis or PsA are at a 2- to 4-fold increased risk of developing CD and a 2- to 3-fold increased risk of developing UC. Additionally, in patients with AS, there is a 3- to 5-fold increased risk of IBD compared with the general population. Secukinumab is approved for the treatment of psoriasis, PsA, and AS and is a fully human monoclonal antibody that neutralizes interleukin-17A. Here, we report the pooled incidence of IBD, CD, and UC in patients with psoriasis, PsA, or AS who received IL-17A inhibition with secukinumab. The data reported herein are based on results from 21 Phase III/IV clinical trials of secukinumab for psoriasis, PsA, or AS.

Methods: This analysis evaluated pooled data from 14 Phase III and one Phase IV psoriasis trials, three Phase III PsA trials, and three Phase III AS trials. Patients with a history of IBD but not active IBD were eligible for enrollment in these trials. Data from all patients that received at least one dose of secukinumab were included in this analysis. IBD reporting includes cases of CD, UC, and IBD not otherwise specified (NOS).

Results: A total of 7,355 patients receiving secukinumab were assessed for the presence of IBD: 5,181 with psoriasis, 1,380 with PsA, and 794 with AS. Over the entire treatment period, the mean total exposure to secukinumab was 10,416.9 patient-years in patients with psoriasis, 3,866.9 patient-years in patients with PsA, and 1,943.1 patient-years in patients with AS. The exposure-adjusted incidence rate (EAIR) per 100 patient-years (95% confidence interval [CI]) of CD, UC, and IBD NOS in secukinumab-treated patients were 0.05 [0.02, 0.11], 0.13 [0.07, 0.23], and 0.01 [0.00, 0.05], respectively, in the psoriasis studies; 0.08 [0.02, 0.23], 0.08 [0.02, 0.23], and 0.05 [0.01, 0.19], respectively in the PsA studies; and 0.4 [0.2, 0.8], 0.2 [0.1, 0.5], and 0.1 [0.0, 0.3], respectively, in the AS studies. Additionally, the incidence of IBD, CD, and UC did not increase over time.

Conclusion: Pooled data from 21 studies indicated that the observed exposure-adjusted incidence rates of IBD, CD, and UC with secukinumab were low and did not increase over time in patients with moderate-to-severe plaque psoriasis, PsA, or AS.

Funding: This research was sponsored by Novartis Pharma AG, Basel, Switzerland.

Clinical efficacy of tildrakizumab, an anti–IL-23p19 monoclonal antibody, in patients with chronic plaque psoriasis over two years of treatment: Results from long-term extensions to two Phase III clinical studies (reSURFACE 1 and reSURFACE 2)

Clinical efficacy of tildrakizumab, an anti–IL-23p19 monoclonal antibody, in patients with chronic plaque psoriasis over two years of treatment: Results from long-term extensions to two Phase III clinical studies (reSURFACE 1 and reSURFACE 2)

Presenters: Papp K1, Reich K2, Blauvelt A3, Thaçi D4, Sinclair R5, Tyring SK6, Cichanowitz N7, Green S7, Li Q,7 La Rosa C7

Affiliations: 1Probity Medical Research, Waterloo, ON, Canada; 2SCIderm Research Institute and Dermatologikum Hamburg, Hamburg, Germany; 3Oregon Medical Research Center, Portland, Oregon; 4Comprehensive Center for Inflammation Medicine, University Medical School Schleswig-Holstein, University of Lübeck, Lübeck, Germany; 5University of Melbourne, Melbourne, VIC, Australia; 6Department of Dermatology, University of Texas, Houston, Texas; 7Merck & Co., Inc., Kenilworth, New Jersey

Background/Objective: Tildrakizumab is a high-affinity, humanized, anti-IL-23p19 monoclonal antibody that has demonstrated efficacy in the treatment of chronic plaque psoriasis in two Phase III studies (reSURFACE 1 and 2). Extensions of these studies are ongoing. In this analysis, we present preliminary data evaluating maintenance of response in patients who were responders to tildrakizumab upon entering the extension periods and who maintained response a year into the extensions (a total of at least 2 years of treatment).

Methods: The reSURFACE base studies are three-part, double-blinded, randomized, placebo-controlled studies in adult patients with moderate-to-severe chronic plaque psoriasis (body surface area involvement ?10%, Physician’s Global Assessment [PGA] score ?3, and Psoriasis Area and Severity Index [PASI] ?12). Tildrakizumab 200mg and 100mg were evaluated for 64 weeks (reSURFACE 1; NCT01722331) and 52 weeks (reSURFACE 2; NCT01729754), respectively. Patients were eligible for the optional long-term extensions if they completed the base studies and achieved PASI ?50 at the end of the base studies (for reSURFACE 1 only, patients had to have received an active dose of tildrakizumab within 12 weeks of the end of the base study). Patients received the same dose of tildrakizumab (200mg or 100mg every 12 weeks) as they received at the completion of the base studies. Administration was open label after database lock for the base studies. The full analysis set (patients with at least 1 dose of extension treatment based on assigned treatment) was the primary efficacy population. The efficacy objective during the extension period was evaluation of maintenance of efficacy endpoints (i.e., proportion of PASI 50, 75, 90, and 100 responders 1 year into the extension among PASI 50, 75, 90, and 100 responders at the start of the extension) prespecified to be based on observed data. No statistical analyses were planned for comparison between doses.

Results: In reSURFACE 1, 772 patients entered, 638 completed the base study, and 506 entered the extension; in reSURFACE 2, 1,090 patients entered, 756 patients completed the base study, and 731 entered the extension. In reSURFACE 1, in patients entering the extension on tildrakizumab 200mg, PASI 50/75/90/100 was maintained by 97%/91%/82%/63% (out of 255/208/135/70 patients with data at 1 year); in patients on tildrakizumab 100mg, PASI 50/75/90/100 was maintained by 98%/90%/74%/53% (out of 219/195/121/70 patients with data at 1 year). In patients entering the extension on tildrakizumab 200 mg in reSURFACE 2, PASI 50/75/90/100 was maintained by and 97%/88%/84%/70% (out of 330/293/191/97 patients with data at 1 year); for those on tildrakizumab 100mg, PASI 50/75/90/100 was maintained by 99%/92%/84%/66% (out of 352/327/249/125 patients with data at 1 year).

Conclusion: Tildrakizumab 100mg and 200mg demonstrated maintenance of efficacy in the treatment of moderate-to-severe chronic plaque psoriasis for at least two years of treatment.

Funding: Study sponsored by Merck & Co. Analyses previously presented at the 26th European Academy of Dermatology and Venereology Congress, Geneva, Switzerland, 2017.

Sustained and improved efficacy of tildrakizumab from Week 28 to Week 52 in treating moderate-to-severe plaque psoriasis

Sustained and improved efficacy of tildrakizumab from Week 28 to Week 52 in treating moderate-to-severe plaque psoriasis

Presenters: Elewski B1, Menter M2, Crowley J3, Tyring J4, Zhao Y5, Lowry S5, Rozzo S5, Mendelsohn A5, Parno J5, Gordon K6

Affiliations: 1Department of Dermatology, The University of Alabama at Birmingham, Birmingham, AL; 2Division of Dermatology, Baylor University Medical Center, Dallas, TX; 3Bakersfield Dermatology, Bakersfield, CA; 4Department of Dermatology, University of Texas Health Science Center, Houston, TX; 5Sun Pharmaceuticals, Princeton, NJ; 6Medical College of Wisconsin, Milwaukee, WI

Introduction: Two Phase III, double-blind, randomized controlled trials (reSURFACE 1: NCT01722331; reSURFACE 2: NCT01729754) have demonstrated efficacy and safety of tildrakizumab, a high affinity, humanized, IgG1 ?, anti-interleukin-23 monoclonal antibody, in the treatment of adult patients with moderate-to-severe plaque psoriasis over 28 weeks. This analysis evaluated longer-term data from these two trials to examine whether the efficacy is sustained or improved from Week 28 to Week 52.

Methods: Both trials randomized adult patients with moderate-to-severe plaque psoriasis to receive tildrakizumab 100mg or 200mg at Weeks 0 and 4, then every 12 weeks after Week 4. At Week 28, patients with a Psoriasis Area and Severity Index (PASI) response of at least 50 percent were re-randomized, based on their Week 28 PASI response, to receive a higher dose, a lower dose, or an unchanged dose of tildrakizumab or placebo (randomized withdrawal in reSURFACE 1 per the trial designs). The current analysis evaluated only patients treated with the same dose of tildrakizumab (100mg or 200mg) throughout the first 52 weeks. Four mutually exclusive groups were created based on Week 28 PASI response: PASI 100, PASI 90–99, PASI 75–89 and PASI 50–74. PASI responses at Week 52 (observed data) were analyzed for each Week 28 PASI-response group.

Results: This analysis included 352 patients on tildrakizumab 100mg (men: 69.9%; mean baseline age: 44.9 years) and 313 on tildrakizumab 200mg (men: 67.1%; mean baseline age: 46.4 years). The proportions of patients achieving PASI 100, PASI 90–99, PASI 75–89 and PASI 50–74 at Week 28 were 25.9 percent, 38.4 percent, 25.3 percent, and 10.5 percent, respectively, for those on the 100mg dose, and 24.6 percent, 24.3 percent, 19.5 percent and 31.6 percent, respectively, for those on the 200mg dose. Among patients who achieved Week 28 PASI of at least 90 with either dose of tildrakizumab, 88.9 to 89.4 percent maintained PASI of at least 90 at Week 52. Overall, 91.1 percent of patients on the 100mg dose and 93.9 percent on the 200mg dose with Week 28 PASI of at least 75 maintained PASI of at least 75 at Week 52. In addition, 39.3 to 40.4 percent of patients with Week 28 PASI 75 to 89 remained PASI 75 to 89 at Week 52 and 33.7 to 41.0 percent improved to PASI of at least 90. Among patients with Week 28 PASI 50 to 74, 20.2 to 29.7 percent achieved PASI of at least 90 and 52.5 to 64.9 percent achieved PASI of at least 75 at Week 52. Overall, only 2.6 percent of patients on the 100mg (n=9/352) or 200mg (n=8/313) dose had Week 52 PASI less than 50.

Conclusion: Among patients with moderate-to-severe plaque psoriasis treated with tildrakizumab 100mg or 200mg at Weeks 0 and 4, then every 12 weeks after Week 4, those who achieved Week 28 PASI of at least 50 and continued on the same dose had sustained or improved efficacy from Week 28 to Week 52. The majority patients who achieved Week 28 PASI of at least 75 or 90 maintained PASI 75 or 90 at Week 52. More than half of partial responders (PASI 50–74) at Week 28 eventually achieved PASI of at least 75 and at least one in five achieved PASI of at least 90 at Week 52.