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.

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.

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.

Certolizumab pegol is effective for chronic plaque psoriasis across patient subgroups: a pooled analysis from ongoing, Phase III studies (CIMPASI-1 and CIMPASI-2)

Presenters: Reich K¹, Blauvelt A², Thaçi D³, Leonardi C⁴, Poulin Y⁵, Burge D⁶, Peterson L⁷, Drew J⁶, Arendt C⁸, Gottlieb AB⁹

Affiliations: ¹Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany; ²Oregon Medical Research Center, Portland, OR; ³University of Lübeck, Lübeck, Germany; ⁴Central Dermatology and Saint Louis University School of Medicine, St. Louis, MO; ⁵Centre de Recherche Dermatologique du Québec Métropolitain, Québec, Canada; ⁶Dermira, Inc., Menlo Park, CA; ⁷UCB Pharma, Raleigh, NC; ⁸UCB Pharma, Brussels, Belgium; ⁹New York Medical College at Metropolitan Hospital, New York, NY

Background/Objective: CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272) are ongoing Phase III trials of certolizumab pegol (CZP) in adults with moderate-to-severe chronic plaque psoriasis. This prespecified, pooled subgroup analysis is assessing efficacy of CZP to Week 48 across demographic and baseline disease characteristic subgroups.

Methods: Patients are at least 18 years old with moderate-to-severe plaque psoriasis for at least six months (Psoriasis Area and Severity Index [PASI] ?12, Body Surface Area Affected [BSA] ?10%, Physician’s Global Assessment [PGA] ?3 on a 5-point scale), had no prior exposure to CZP or less than two biologics, and were candidates for systemic psoriasis therapy. The coprimary endpoints were PASI 75 (?75% reduction in PASI) and PGA 0/1 (clear/almost clear with ?2 category improvement in PGA) at Week 16. Subgroup analyses based on age, sex, weight, body mass index (BMI), duration of psoriasis, baseline PASI, and baseline BSA affected were performed at Week 48. PASI 75, PGA 0/1, and PASI 90 (?90% reduction in PASI) responses were summarized at Week 16 using a logistic regression model with multiple imputation (overall population) and descriptively at Week 48 based on nonresponse imputation (subgroups).

Results: Patients are being randomized to CZP 400mg every two weeks (Q2W; n=175), CZP 200mg Q2W (following 400mg loading dose at Weeks 0, 2, and 4; N=186), or placebo (n=100). So far, at Week 16 PASI 75 responder rates for CZP 400mg Q2W and CZP 200mg Q2W were 82.0 percent and 76.7 percent, respectively, versus 9.9 percent for placebo (both p<0.0001), and PGA 0/1 responder rates for CZP 400mg Q2W and CZP 200mg Q2W were 65.3 percent and 56.8 percent, respectively, versus 2.7 percent for placebo (both p<0.0001). At Week 48, CZP 400mg Q2W and CZP 200mg Q2W responder rates were 83.6 percent and 70.7 percent for PASI 75, 68.9 percent and 61.0 percent for PGA 0/1, and 61.6 percent and 50.0 percent for PASI 90. Efficacy was observed for both CZP 400mg Q2W and 200mg Q2W across demographic and baseline disease characteristic subgroups. CZP is generally well tolerated and there have been few serious treatment-emergent adverse events (TEAEs) or discontinuations due to TEAEs; no new safety signals have been observed.

Conclusion: In this pooled analysis of CIMPASI-1 and CIMPASI-2, treatment with either dose of CZP thus far is resulting in statistically significant and clinically meaningful improvements in signs and symptoms of psoriasis at Week 16 that have been maintained at Week 48. The safety profile for CZP is consistent with the anti-TNF class in psoriasis and the known safety profile of CZP. Similar to the overall population, PASI 75, PGA 0/1, and PASI 90 responder rates have been numerically greater for CZP 400 mg Q2W versus 200 mg Q2W across most subgroups at Week 48.

Impact on quality of life and satisfaction with apremilast in patients with moderate plaque psoriasis: 52-week results of the UNVEIL study

Presenters: Gold LS¹, Forman S², Lebwohl M³, Jackson JM⁴, Goncalves J⁵, Levi E⁵, Bagel J⁶

Affiliations: ¹Henry Ford Health System, West BloomTeld, MI; ²Forward Clinical Trials, Tampa, FL; ³Icahn School of Medicine at Mount Sinai, New York, NY; ⁴University of Louisville, Forefront Dermatology, Louisville, KY; ⁵Celgene Corporation, Summit, NJ; ⁶Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ

Background/Objective: Patients with moderate plaque psoriasis (i.e., 5–10% psoriasis-involved body surface area [BSA]) often receive no treatment or are undertreated with topical monotherapy. Patients with moderate psoriasis often report substantial impairments in disease-related quality of life (QoL), despite having lower psoriasis-involved BSA. Among the symptoms of psoriasis, pruritus is a key contributor to QoL impairments. Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, improved QoL and disease severity, with acceptable tolerability, in Phase III clinical studies of patients with moderate-to-severe psoriasis. Evaluating Apremilast in a Phase IV Trial of Efficacy and Safety in Patients With Moderate Plaque Psoriasis (UNVEIL; ClinicalTrials.gov: NCT02425826), the first prospective, randomized, placebo (PBO)-controlled trial in systemic- and biologic-naive patients with moderate plaque psoriasis, demonstrated that apremilast 30mg twice-daily (APR) was effective, generally well tolerated, and had a positive impact on QoL during the 16-week, double-blind, PBO-controlled phase. The improvements in QoL and pruritus as well as treatment satisfaction are described for the open-label APR treatment phase (Weeks 16 to 52) of UNVEIL.

Methods: UNVEIL is a Phase IV, multicenter, randomized, PBO-controlled, double-blind study. Adult men and women with chronic plaque psoriasis for at least six months before screening were included in the study. Moderate plaque psoriasis at screening and baseline as defined by a BSA of 5 to 10 percent and static Physician’s Global Assessment (sPGA) of 3 (moderate) based on a scale ranging from 0 (clear) to 5 (very severe). Subject selected had no prior exposure to systemic or biologic treatments for psoriasis, psoriatic arthritis, or any other condition that could affect the assessment of psoriasis. Exclusion criteria included presence of inflammatory or dermatologic conditions, including forms of psoriasis other than plaque psoriasis. Individuals who had undergone topical therapy within two weeks or phototherapy within four weeks of randomization were also excluded. Patients were randomized (2:1) to receive APR or PBO during Weeks 0 to 16; patients in the PBO group were switched to APR at Week 16. All patients continued taking APR through Week 52. An unmedicated moisturizer was the only topical therapy permitted during the study.

Patients completed the Dermatology Life Quality Index (DLQI), Pruritus Visual Analog Scale (VAS), and Treatment Satisfaction Questionnaire for Medication (TSQM) version II. QoL was assessed with the DLQI, a validated instrument containing ten items pertaining to the skin and designed to assess QoL in a dermatology clinical setting. QoL endpoints included mean change from baseline in DLQI total score at Week 16 and Week 52, proportion of patients with baseline DLQI greater than 5 who achieved DLQI response (i.e., minimal clinically important difference [MCID] defined as a 5-point improvement from baseline in DLQI total score among patients with baseline DLQI >5). Pruritus was assessed on a 100mm VAS ranging from “no itch” (0) to “itch as severe as can be imagined” (100). Pruritus endpoints included mean change from baseline in pruritus VAS at Week 16 and Week 52. Treatment satisfaction was assessed using the TSQM Version II, a validated, self-administered, 11-question instrument designed to evaluate patient satisfaction with current treatment. An algorithm was used to transform scores to a 0- to 100-scale for effectiveness, side effects, convenience, and global satisfaction, with higher scores indicating greater satisfaction. Mean TSQM scores for effectiveness, side effects, convenience, and global satisfaction were assessed at Week 16 and Week 52. Safety was evaluated based on adverse events (AEs), vital signs, clinical laboratory testing, and complete physical examinations. QOL, pruritus, and treatment satisfaction assessments at Week 16 were conducted for the intent-to-treat (ITT) population, which included all randomized patients. At Week 52, efficacy analyses were performed in the modified ITT population (all patients who entered the APR extension phase and were treated). Safety assessments were conducted in all randomized patients who received one dose of study medication. Changes from baseline in DLQI total score and pruritus VAS score at Week 16 were compared between the APR and PBO groups using a two-way analysis of covariance (ANOVA) model with treatment and site as factors and baseline value as a covariate. The proportions of patients achieving a DLQI response at Week 16 were compared between groups using a two-sided Cochran-Mantel-Haenszel test stratified by site. Mean TSQM scores at Week 16 were compared between treatment groups by ANOVA with treatment and site as factors. QOL, pruritus, and treatment satisfaction parameters at Week 52 were evaluated descriptively. The last-observation-carried-forward (LOCF) methodology was used to impute missing values. Safety assessments were summarized using frequencies and percentages.

Results: A total of 221 patients were randomized to study treatment, constituting the ITT population; 185 patients (84%) completed the PBO-controlled phase (Weeks 0–16) and 136/185 patients (74%) completed the APR treatment phase (Weeks 16–52). Demographics and baseline disease characteristics were generally similar between treatment groups. At baseline, mean DLQI total score was comparable between treatment groups, and mean pruritus VAS score was slightly higher in the PBO group. At Week 16, improvement from baseline in DLQI total score was significantly greater with APR than with PBO (-4.8 vs. -2.4; P=0.0008). Significantly more patients with a baseline DLQI total score greater than 5 who received APR versus PBO achieved the DLQI MCID at Week 16 (63.8% vs. 34.5%; P=0.0009). At Week 52, improvement in DLQI total score was maintained in patients who were randomized to APR and then continued on APR during the open-label APR treatment phase (mean change from baseline: -4.4). Patients who switched from PBO to APR at Week 16 achieved similar improvements in DLQI total score at Week 52 (mean change from baseline: -5.1). Among patients who were initially randomized to APR at baseline, the percentages of patients who achieved DLQI MCID at Week 16 were maintained over 52 weeks. At Week 16, mean change from baseline in pruritus VAS score was -19.2mm in the APR group and -10.2mm in the PBO group (P=0.0016). The improvement in pruritus VAS score was maintained at Week 52 in patients who continued on APR, and mean VAS score improved in those switched from PBO to APR. At Week 16, treatment effectiveness, as measured by the TSQM, was significantly greater with APR than with PBO (P<0.0001). Global satisfaction also favored APR over PBO (P<0.0001), whereas satisfaction with side effects (P=0.34) and convenience (P=0.63) did not differ between treatment groups. At Week 52, levels of satisfaction were maintained on all domains. The most common AEs reported with APR treatment from 0 to 52 weeks included diarrhea, nausea, headache, and nasopharyngitis; most AEs were mild or moderate in severity. Exposure-adjusted incidence rates (EAIR) per 100 patient-years did not increase with longer exposure up to 52 weeks. No new safety or tolerability signals were observed up to 52 weeks.

Conclusion: APR improved QoL and reduced pruritus at Week 16 in systemic- and biologic-naive patients with moderate plaque psoriasis (BSA 5–10%); these improvements were maintained over 52 weeks with continued APR treatment. The beneficial effects of APR on QoL and pruritus were consistent with those previously reported in patients with moderate-to-severe plaque psoriasis in randomized Phase III trials. Global treatment satisfaction was greater with APR than with PBO at Week 16, and satisfaction remained high over 52 weeks of APR treatment. The safety and tolerability of APR was consistent with previous studies. No new safety or tolerability issues were observed with APR treatment up to Week 52.

Funding/Disclosures: The authors acknowledge financial support for this study from Celgene Corporation. Linda Stein Gold is an investigator and/or consultant for Celgene Corporation. Seth Forman provides research support for Celgene Corporation. Mark Lebwohl is affiliated with Mount Sinai, which receives funds from Celgene Corporation. J. Mark Jackson is a consultant, receives honoraria from, provides research support and/or other support to Celgene Corporation. Joana Goncalves and Eugenia Levi are employees of the Celgene Corporation. Jerry Bagel is an advisory board member, speaker, consultant, and/or provider of research support for Celgene Corporation.