Maintenance of response with certolizumab pegol for the treatment of chronic plaque psoriasis: 48-week results from two ongoing Phase III, multicenter, randomized, placebo-controlled 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 BioSciences, Inc., Raleigh, NC; ⁸UCB Pharma, Brussels, Belgium; ⁹New York Medical College, Valhalla, NY

Introduction: Psoriasis affects approximately three percent of adults in the United States and approximately 2 to 6 percent in Europe, and most patients develop the disease in the third decade of life. Therapy for patients with chronic plaque psoriasis varies per the severity of the disease, with topical therapies and/or phototherapy used to treat limited or mild psoriasis, and photochemotherapy, cyclosporine, methotrexate, apremilast, or biologics (e.g., tumor necrosis factor (TNF) inhibitors,

anti?IL17s, and anti?IL12/23s) used to treat moderate-to-severe forms. Certolizumab pegol (CZP) is the only PEGylated, Fc-free, anti-TNF biologic currently under development for the treatment of moderate-to-severe chronic plaque psoriasis and has demonstrated positive results in previous psoriasis trials. CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272) are ongoing Phase III trials designed to assess the efficacy and safety of CZP compared with placebo; results from the first 48 weeks of the two studies are presented here.

Methods: CIMPASI-1 and CIMPASI-2 are replicate, Phase III multicenter studies conducted in North America and Europe, consisting of randomized, double-blind, placebo-controlled periods for the first 48 weeks followed by 96 weeks of open-label observation. Patients were randomized 2:2:1 to CZP 400mg every two weeks (Q2W), CZP 200mg Q2W (following 400mg loading dose at Weeks 0, 2, 4), or placebo Q2W for 16 weeks. At Week 16, the following patients continued to receive treatment through Week 48: CZP 400mg Q2W- and CZP 200mg Q2W-treated Psoriasis Area and Severity Index (PASI) 50 responders (?50% reduction in PASI) continued to receive their initial blinded treatment; placebo-treated Week 16 PASI 75 responders (?75% reduction in PASI) continued blinded placebo treatment; PASI 50 to 75 responders (?50% but <75% reduction in PASI) received CZP 200mg Q2W (following 400mg loading dose at Weeks 16, 18, 20); PASI 50 nonresponders at Week 16 entered the Escape Arm and received unblinded CZP 400mg Q2W; PASI 50 nonresponders at Week 32, 40, or 48 were withdrawn from the study. Eligible patients were at least 18 years of age and had moderate-to-severe chronic plaque psoriasis for at least six months (PASI ?12, Body Surface Area (BSA) ?10%, Physician’s Global Assessment [PGA; 5-point scale] ?3). Patients had to be candidates for systemic psoriasis therapy, phototherapy, and/or photochemotherapy. Patients were excluded if they had previous treatment with CZP or more than two biologics (including anti-TNF); had history of primary failure to any biologic or secondary failure to more than one biologic; had erythrodermic, guttate, or generalized pustular psoriasis types; or had history of current, chronic, or recurrent viral, bacterial, or fungal infections. Coprimary endpoints were PASI 75 and PGA 0/1 (“clear” or “almost clear” with ?2-category improvement) at Week 16. Secondary endpoints reported here were PASI 90 at Week 16 and PASI 75 and PGA 0/1 at Week 48; PASI 90 at Week 48 was included as an additional endpoint. All efficacy analyses were performed on the Randomized Set (all randomized patients). Logistic regression models with factors of treatment group, region, and prior biologic exposure (yes/no) were used to analyze PASI 75, PGA 0/1, and PASI 90 responder rates (Week 16). The Markov chain Monte Carlo (MCMC) method for multiple imputation was used to account for missing data. Safety assessments were performed on the Safety Set, which included all randomized patients who received at least one dose of study medication.

Results: In both studies, at least 90 percent of patients in each treatment arm completed Week 16, and the highest Week 16 completion rates were in the CZP 400mg Q2W treatment group. Of those patients who entered the blinded Maintenance Period in CIMPASI-1/CIMPASI-2, 90.9 percent/88.4 percent of CZP 400mg Q2W patients and 95.9 percent/84.2 percent CZP 200mg Q2W patients completed Week 48. Baseline PASI and PGA scores were comparable across treatment groups for both studies. Roughly one-third of study participants reported prior biologic use, and the proportion across treatment arms was similar. At Week 16, responder rates were greater for CZP 400mg Q2W and CZP 200mg Q2W versus placebo for PASI 75 and PGA 0/1 (p<0.0001 for all). CZP 400mg Q2W and CZP 200mg Q2W PASI 75 responder rates were maintained to Week 48. PGA 0/1 responder rates were also maintained to Week 48 for patients who continued to receive either dose of CZP during the Maintenance Period. At Week 16, PASI 90 responder rates were greater for CZP 400mg Q2W and 200mg Q2W versus placebo (p<0.0001 for both). PASI 90 responder rates continued to improve beyond Week 16, and the difference between dose groups increased by Week 48. For CZP 400mg Q2W and CZP 200mg Q2W versus placebo, treatment-emergent adverse events (TEAE)/serious TEAE incidence rates per 100 patient?years from baseline to Week 16 were 375.9/19.0 and 292.3/6.9 versus 297.1/6.8 in CIMPASI-1, and 405.7/15.3 and 308.7/7.4 versus 388.9/0 in CIMPASI-2. For CZP 400mg Q2W and CZP 200mg Q2W, TEAE/serious TEAE incidence rates per 100 patient-years was lower from baseline to Week 48 compared with rates per 100 patient-years from baseline to Week 16 (257.6/10.4 and 218.3/5.3 in CIMPASI-1, and 277.5/7.5 and 236.0/9.7 in CIMPASI-2). One serious infection was reported in the CZP 400mg Q2W group in CIMPASI-1, and one in the

CZP 400mg Q2W group in CIMPASI-2. One death, due to motor vehicle accident, was reported in the

CZP 400mg Q2W group in CIMPASI?1. After 48 weeks of treatment, TEAEs occurring in over 10 percent of all CZP-treated patients were nasopharyngitis and upper respiratory tract infection.

Conclusion: Treatment with CZP 400mg Q2W or CZP 200mg Q2W for 16 weeks was associated with statistically significant, clinically meaningful improvements for all endpoints analyzed (PASI 75, PGA 0/1, and PASI 90) compared to placebo. Response rates were maintained at Week 48 with both CZP doses. For most measures, improvement at both Week 16 and Week 48 was numerically greatest in patients receiving CZP 400mg Q2W. TEAEs were consistent with the known safety profile of anti-TNF therapy, and no new safety signals were observed with CZP at any dose over 48 weeks.

Funding/Disclosures: This study and all costs associated with the development of this poster were funded by Dermira, Inc. Andrew Blauvelt and Diamant Thaçi receive consulting honoraria, are clinical investigators for and/or receive speaker’s fees from Dermira, Inc. Daniel Burge and Janice Drew are employees of Dermira, Inc. Alice B. Gottlieb holds consulting and/or advisory board agreements with Dermira, Inc.

Improvement in scalp and nails with apremilast in patients with moderate plaque psoriasis naive to systemic and biologic therapy: 52-week results of the UNVEIL study.

Presenters: Jackson JM¹, Alikhan A², Lebwohl M³, Stein Gold L⁴, Levi E⁵, Bagel J⁶,

Affiliations: ¹University of Louisville, Forefront Dermatology, Louisville, KY; ²University of Cincinnati, Department of Dermatology, Cincinnati, OH; ³Icahn School of Medicine at Mount Sinai, New York, NY; ⁴Henry Ford Health System, West Bloomfield, MI; 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. Plaque psoriasis that occurs in difficult-to-treat areas such as the scalp and nails might be disproportionately more distressing to patients because it is highly visible and can severely impact daily functioning. Apremilast is an oral, small-molecule phosphodiesterase 4 inhibitor that works intracellularly to regulate inflammatory pathways relevant to the pathogenesis of psoriasis. Apremilast has been shown to be effective and has demonstrated acceptable tolerability in Phase IV clinical studies in 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) is the first prospective, randomized, placebo (PBO)-controlled trial to demonstrate the clinical efficacy and safety of a systemic treatment (apremilast) in systemic- and biologic-naive patients with moderate plaque psoriasis. To further understand the efficacy of apremilast in patients with moderate plaque psoriasis, analyses were performed in the subset of patients with baseline scalp and/or nail involvement.

Methods: UNVEIL is a Phase IV, multicenter, randomized, PBO-controlled, double-blind study. Men and women at least 18 years of age with chronic plaque psoriasis for six months before screening were included in the study. Subjects had moderate plaque psoriasis at screening and baseline as defined by 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). Included subjects had no prior exposure to systemic or biologic treatments for psoriasis, psoriatic arthritis, or any other condition that could affect the assessment of psoriasis. Potential subjects with an inflammatory or dermatologic condition, including forms of psoriasis other than plaque psoriasis, were excluded. Persons using topical therapy within two weeks or phototherapy within four weeks of randomization were also excluded. Patients were randomized (2:1) to receive apremilast 30mg twice daily (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. A nonmedicated moisturizer was the only topical therapy permitted during the study.

Patients with a baseline Scalp Physician Global Assessment (ScPGA) score of 1 or a Nail Psoriasis Severity Index (NAPSI) score of 1 in the target nail were included in subanalyses of scalp and nail involvement. ScPGA was assessed on a 6-point scale ranging from 0 (clear) to 5 (very severe). One thumbnail or fingernail with the worst nail psoriasis involvement at baseline was designated as the target nail. NAPSI score was calculated in the target nail as the sum of scores for the nail matrix and nail bed, with each score based on the number of quadrants with psoriasis features. Efficacy assessments in patients with scalp psoriasis at baseline included proportion of patients achieving ScPGA score of 0 (clear) or 1 (minimal), with a 2-point reduction from baseline score, at Week 16 and Week 52. Efficacy assessments in patients with nail psoriasis at baseline included change from baseline in NAPSI score at Week 16 and Week 52, proportion of patients achieving a 50-percent reduction from baseline in NAPSI score (NAPSI-50) at Week 16 and Week 52. Safety was evaluated based on adverse events (AEs), vital signs, clinical laboratory testing, and complete physical examinations. Efficacy and safety assessments were conducted for the intent-to-treat (ITT) population, which included all randomized patients; safety assessments included all patients who received one dose of study medication. The proportions of patients achieving ScPGA and NAPSI-50 responses were compared between the PBO and APR groups at Week 16 using a two-sided Cochran-Mantel-Haenszel test stratified by site. Changes from baseline in NAPSI score at Week 16 were compared between treatment groups using a two-way analysis of covariance (ANCOVA) model with treatment and site as factors and baseline value as a covariate. Efficacy 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. Of these, 167 patients (75.6%) had scalp psoriasis and 83 patients (37.6%) had nail psoriasis at baseline. Demographic and baseline disease characteristics of the cohorts with scalp psoriasis or nail psoriasis were generally comparable between treatment groups. Mean baseline NAPSI scores were comparable between treatment groups. Across treatment groups, most patients had mild or moderate scalp involvement (i.e., ScPGA score of 2 or 3). Regarding efficacy of APR in scalp psoriasis, at Week 16, more patients treated with APR than with PBO achieved an ScPGA score of 0 or 1 with a 2-point reduction from baseline (38.4% vs. 20.0%, P=0.0178). At Week 52, patients remaining on APR maintained ScPGA response, and those who switched to APR from PBO at Week 16 (PBO/APR) demonstrated an improvement in ScPGA response comparable to those who continued APR treatment (APR/APR). An ScPGA score of 0 or 1 with a 2-point reduction from baseline was achieved by 47.7 percent of patients randomized to APR who continued on APR (APR/APR), and 46.9 percent of patients randomized to PBO who switched to APR (PBO/APR). Regarding the efficacy of APR in nail psoriasis, at Week 16, the mean percentage change from baseline in NAPSI score was -10.5 percent in the PBO group and -28.9 percent in the APR group (P=0.12). At Week 52, continued improvement in NAPSI score was seen in patients who remained on APR treatment (mean percentage change from baseline, -51.9%). Patients who switched from PBO to APR at Week 16 demonstrated an improvement in NAPSI score (mean percentage change from baseline, -52.7%). At Week 16, NAPSI-50 response was achieved by 18.5 percent of patients in the PBO group and 26.8 percent of patients in the APR group (P=0.50). Although differences in NAPSI-50 response with APR compared with PBO are numerically greater, the number of patients with nail psoriasis at baseline was low and thus statistical significance was not demonstrated. At Week 52, the proportion of patients who achieved NAPSI-50 response increased in patients who remained on APR treatment and in patients who switched to APR from PBO at Week 16.

The most common AEs reported with APR treatment from 0 to 52 weeks were diarrhea, nausea, headache, and nasopharyngitis. Most AEs were mild or moderate; discontinuations due to AEs occurred in 6.6 percent of patients over the 52-week study. The incidence of AEs, based on exposure-adjusted incidence rate (EAIR) per 100 patient-years, did not increase with longer exposure up to 52 weeks when compared with Weeks 0 to 16. No new safety or tolerability issues were observed up to 52 weeks.

Conclusion: APR treatment improved scalp and nail psoriasis at Week 16 in systemic- and biologic-naive patients with moderate plaque psoriasis (BSA 5–10%); continued improvement was seen with APR treatment up to 52 weeks. The efficacy of APR on scalp and nail psoriasis was consistent with that previously reported in patients with moderate-to-severe plaque psoriasis in randomized Phase III trials. The safety and tolerability profile of APR was also consistent with previous studies.

Funding/Disclosures: The authors acknowledge financial support for this study from Celgene Corporation. J. Mark Jackson provides research, honoraria, consulting, and/or other support to the Celgene Corporation. Ali Alikhan is a former speaker for Celgene Corporation. Mark Lebwohl is an investigator and/or consultant for the Celgene Corporation. Linda Stein Gold is an investigator and/or consultant for the Celgene Corporation. Joana Goncalves and Eugenia Levi are employees of the Celgene Corporation. Jerry Bagel is an advisory board member, speaker, consultant, and/or provides research support to the Celgene Corporation.