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

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.

Long-term safety of adalimumab (HUMIRA) in adult patients from global clinical trials across multiple indications: an updated analysis in 29,987 patients representing 56,951 patient-years

Long-term safety of adalimumab (HUMIRA) in adult patients from global clinical trials across multiple indications: an updated analysis in 29,987 patients representing 56,951 patient-years

Presenters: Burmester GR1, Panaccione R2, Gordon KB3, Rosenbaum J4, Arikan D5, Lau W5, Tarzynski-Potempa R5

Affiliations: 1Charité – University Medicine Berlin, Berlin, Germany; 2University of Calgary, Calgary, AB, Canada; 3Medical College of Wisconsin, Milwaukee, WI; 4Oregon Health & Science University and Legacy Devers Eye Institute, Portland, OR; 5AbbVie, North Chicago, IL

Background/Objective: Adalimumab is an anti–tumor necrosis factor-? (TNF-?) agent indicated for the treatment of immune-mediated diseases. The long-term safety of adalimumab was previously reported in 23,458 patients representing up to 12 years of clinical trial exposure in rheumatoid arthritis (RA), juvenile idiopathic arthritis, ankylosing spondylitis (AS), psoriatic arthritis (PsA), plaque psoriasis (Ps), and Crohn’s disease (CD). Here, we report an updated analysis examining the long-term safety of adalimumab in adult patients with RA, AS, non-radiographic axial spondyloarthritis (nr-axSpA), peripheral SpA (pSpA), PsA, Ps, hidradenitis suppurativa (HS), CD, ulcerative colitis (UC), and non-infectious uveitis (UV).

Methods: Safety data from 78 clinical trials of adalimumab (RA, 33; AS, 5; nr-axSpA, 2; pSpA, 1; PsA, 3; Ps, 13; HS, 3; CD, 11; UC, 4; UV, 2; other, 1) were included in these analyses, including randomized, controlled, open-label, and long-term extension studies conducted in Europe, North America, South America, Asia, Australia, New Zealand, and South Africa through December 31, 2016. Adalimumab postmarketing surveillance data were not included in this analysis. Safety assessments included all adverse events (AEs) and serious AEs (SAEs) that occurred after the first adalimumab study dose and up to 70 days (5 half-lives) after the last study dose.

Results: This analysis included 29,987 patients, representing 56,951 patient-years of exposure. The majority of adalimumab exposure was in RA studies (24,922 PYs). The most frequently reported SAE of interest was infection (highest incidences in CD: 6.9, RA: 4.6, UV: 4.1, and UC: 3.5). The overall standardized mortality ratio was 0.65, 95 percent CI (0.5, 0.74). For most of the adalimumab populations (AS, PsA, Ps, UC, CD, and RA), the observed number of deaths was below what would be expected in an age- and sex-adjusted population. For HS, nr-axSpA, pSpA, and UV studies, the small size of these trials precluded accurate assessment of the standardized mortality ratio, and the 95 percent CIs all included 1.0.

Conclusion: This analysis of data from clinical trials of adalimumab demonstrated an overall safety profile consistent with previous findings and with the TNF inhibitor class. No new safety signals or tolerability issues with adalimumab treatment were identified, and, for most indications, the mortality rate was below what would be expected in an age- and sex-adjusted population. Efficacy and safety data continue to support the well-established benefits of adalimumab for the approved indications.

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

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.

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)

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.

Efficacy and safety of apremilast in systemic- and biologic-naive patients with moderate plaque psoriasis (52-week results of the UNVEIL study)

Efficacy and safety of apremilast in systemic- and biologic-naive patients with moderate plaque psoriasis (52-week results of the UNVEIL study)

Presenters: Strober B1, Forman S2, Bagel J3, Lebwohl M4, Stein Gold L5, Jackson JM6, Goncalves J7, Levi E7, Callis Duffin K8

Affiliations: 1University of Connecticut, Farmington, CT, and Probity Medical Research, Waterloo, ON, Canada; 2Forward Clinical Trials, Tampa, FL; 3Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ; 4Icahn School of Medicine at Mount Sinai, New York, NY; 5Henry Ford Health System, West Bloomfield, MI; 6University of Louisville, Forefront Dermatology, Louisville, KY; 7Celgene Corporation, Summit, NJ; 8University of Utah, Salt Lake City, UT

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. Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has been shown to be effective and has demonstrated acceptable tolerability in patients with moderate-to-severe psoriasis (BSA 10%) in the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) Phase III clinical trial program. 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 an oral systemic treatment (apremilast) in systemic- and biologic-naive patients with moderate plaque psoriasis. Apremilast 30mg twice-daily (APR) was clinically effective and well tolerated during the 16-week, double-blind, PBO-controlled phase. The efficacy and safety results of the open-label APR treatment phase up to Week 52 are presented.

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 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.

The primary efficacy endpoint was the mean percentage change from baseline at Week 16 in PGAxBSA, which represents the product of sPGA and BSA scores. Overall BSA affected by psoriasis is estimated based on the patient’s palm area, which equates to approximately one percent of total BSA. For the 6-point sPGA for plaques in all involved areas, the severity of erythema, scaling, and plaque elevation were each scored; scores were averaged and rounded to the nearest whole number. The secondary efficacy endpoint was the proportions of patients achieving a 75-percent reduction from baseline in PGAxBSA score (PGAxBSA-75) and the sPGA response, defined as a score of 0 (clear) or 1 (almost clear). Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI). Safety was evaluated based on adverse events (AEs), vital signs, clinical laboratory testing, and complete physical examinations. Efficacy and QOL assessments were conducted for the intent-to-treat (ITT) population, which included all randomized patients; safety assessments were conducted in all randomized patients who received one dose of study medication. Mean percentage change from baseline in PGAxBSA and change from baseline in DLQI total score at Week 16 were compared between APR and PBO using a two-sided analysis of covariance model (ANOVA) with treatment and site as factors and baseline value as covariate. PGAxBSA-75 and sPGA responses at Week 16 were evaluated with two-sided Cochran-Mantel-Haenszel tests stratified by site. Efficacy and QOL parameters at Week 52 were evaluated descriptively. Week 16 and Week 52 APR/APR analyses were performed with the ITT population. Week 52 PBO/APR analyses were performed with the modified ITT population (all patients who entered the APR extension phase). The last-observation-carried-forward 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 and constitute 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 the mean pruritus Visual Analog Scale (VAS) score was slightly higher in the PBO group. At Week 16, significantly greater improvement in PGAxBSA occurred in patients receiving APR (-48.1%) versus PBO (-10.2%). At Week 52, improvement was maintained in the APR/APR group and emerged in the PBO/APR group after switching to APR. Significantly more patients treated with APR achieved PGAxBSA-75 response at Week 16 (35.4%) versus PBO (12.3%). PGAxBSA-75 response was maintained in the open-label APR treatment phase. Significantly more patients treated with APR achieved an sPGA score of 0 or 1 at Week 16 (30.4%) versus PBO (9.6%). Long-term sPGA response was maintained with APR treatment in the open-label treatment phase. Improvement in DLQI was significantly greater with APR (-4.8) than PBO (-2.4) at Week 16. DLQI improvement was maintained in patients continuing on APR for up to 52 weeks and developed after patients were switched from PBO to APR. Most AEs were mild or moderate. The most common AEs (reported in 5% of patients in either treatment group during the PBO-controlled period) included diarrhea, headache, nausea, upper respiratory tract infection, decreased appetite, and vomiting.

Conclusion: APR was clinically effective in systemic- and biologic-naive patients with moderate plaque psoriasis (BSA of 5–10%). APR significantly improved PGAxBSA score, PGAxBSA-75 response rate, sPGA 0 or 1 response rate, and DLQI total score at Week 16 compared with PBO. Clinical responses were maintained with continued APR treatment through Week 52 and emerged in patients who switched from PBO to APR at Week 16. The incidence of AEs, based on EAIR per 100 patient-years, did not increase with longer exposure to APR. Safety and tolerability were consistent with previous studies; no new safety or tolerability issues were observed up to 52 weeks.

Funding/Disclosures: The authors acknowledge financial support for this study from Celgene Corporation. Bruce Strober receives honoraria as a consultant, payments (to the University of Connecticut) as an investigator, and is an advisory board member of Celgene Corporation. Seth Forman receives research support from the Celgene Corporation. Jerry Bagel is an advisory board member, speaker, consultant, and/or receives research support from the Celgene Corporation. Mark Lebwohl is an investigator and/or consultant for the Celgene Corporation. J. Mark Jackson receives research, honoraria, consulting, and/or other support from Celgene Corporation. Joana Goncalves and Eugenia Levi are employees of the Celgene Corporation. Kristina Callis Duffin is a consultant, steering committee member, advisory board member, has received grants, and/or has received honoraria from the Celgene Corporation.

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.

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.

Sustained improvement in patient-reported outcomes with continued apremilast treatment over 104 weeks in patients with moderate-to-severe psoriasis

Sustained improvement in patient-reported outcomes with continued apremilast treatment over 104 weeks in patients with moderate-to-severe psoriasis

Presenters: Chapman S1, Cirulli J2, McBride S3

Affiliations: 1Dartmouth–Hitchcock Medical Center, Lebanon, NH; 2Celgene Corporation, Summit, NJ; 3Royal Free London NHS Foundation Trust, London, UK

Background/Objective: Psoriasis is a chronic, systemic, inflammatory disease that is associated with significant impairments in quality of life (QoL), which can include physical discomfort, pruritus, and emotional distress. Apremilast is an oral, small-molecule phosphodiesterase 4 inhibitor that has demonstrated efficacy and safety versus placebo (PBO) in the LIBERATE global Phase IIIb trial in patients with moderate-to-severe plaque psoriasis. Efficacy was maintained for up to 104 weeks in patients who continued treatment with apremilast 30mg twice-daily (APR) in the LIBERATE trial. To further understand the clinical profile of APR, the effect of long-term APR treatment on patient-reported outcomes assessed at 104 weeks was evaluated in the LIBERATE patient population.

Methods: Adults 18 years of age or older with chronic plaque psoriasis for at least 12 months and who were candidates for phototherapy with no prior exposure to biologics for the treatment of psoriatic arthritis or psoriasis were included. Included patients had moderate-to-severe plaque psoriasis, as defined by Psoriasis Area and Severity Index (PASI) score 12, psoriasis-involved Body Surface Area (BSA) 10 percent, and static Physician Global Assessment (sPGA) score 3. Patients included in the study had inadequate response, inability to tolerate, or contraindication to one conventional systemic agent for the treatment of psoriasis. Patients who were excluded had prior treatment with more than three systemic agents for the management of psoriasis, other clinically significant or major uncontrolled diseases, and/or serious infections, including latent, active, or history of incompletely treated tuberculosis. LIBERATE consisted of two treatment phases: a 16-week randomized, double-blind, PBO-controlled phase and an 88-week APR extension phase for an overall treatment duration of 104 weeks. Patients were randomized (1:1:1) to PBO, APR, or etanercept 50mg once-weekly (ETN). At Week 16, all patients in the PBO and ETN groups switched to APR, and patients in the APR group continued APR. Treatment with APR was maintained from Weeks 16 to 104 (APR extension phase).

At Weeks 16 and 104, the proportion of patients achieving response, defined as the minimal clinically important difference (MCID), was evaluated for the following patient-reported outcomes: 1) Dermatology Life Quality Index (DLQI) MCID defined as an at least 5-point decrease from baseline in patients with baseline DLQI score over 5; 2) pruritus Visual Analog Scale (VAS; 0–100mm) MCID defined as an at least 20 percent decrease from baseline; 3) 36-Item Short Form Health Survey version 2 (SF-36v2) Mental and Physical Component Summary scores (MCS and PCS)–both MCIDs defined as an increase of at least 2.5 points from baseline; and 4) Patient Health Questionnaire-8 (PHQ-8)–MCID defined as achievement of score 4 (no significant depressive symptoms). Safety was assessed based on adverse events (AEs), vital signs, clinical laboratory assessments, and physical examinations. Achievement of MCID on the DLQI at Week 16 and Week 104 was a prespecified exploratory endpoint, whereas achievement of MCID on the pruritus VAS, the MCS and PCS, and the PHQ-8 were post-hoc analyses. All MCID analyses were performed using the modified intent-to-treat (mITT) population, which included all randomized patients who received one dose of study medication and had an evaluation at baseline and at the specified time point. Endpoints were analyzed using descriptive statistics, including proportions of patients achieving each endpoint by treatment group; associated 95-percent confidence intervals (CIs) were calculated. All data were analyzed as observed, with no imputation for missing values. The safety population consisted of all patients who were randomized and received one dose of study medication. Descriptive statistics were used for summaries of treatment-emergent AEs and other safety assessments.

Results: The mITT population consisted of 250 patients (PBO, n=84; APR, n=83; ETN, n=83). Patient demographics and baseline disease characteristics were generally comparable between treatment groups. The proportions of patients achieving the MCID for the MCS were generally similar among the treatment groups at Week 16. At Week 104, MCS response was maintained in PBO/APR patients and was comparable between APR/APR and ETN/APR patients at Week 104. At Week 16, the proportion of patients achieving PCS MCID was lowest in the PBO group. At Week 104, PCS response was comparable between the APR/APR and ETN/APR groups and remained lower in the PBO/APR group.

At Week 16 and Week 104, proportions of patients achieving the MCID for PHQ-8 (i.e., score 4 [no significant depressive symptoms]) were generally similar among the treatment groups; response was maintained at Week 104 in the APR/APR group and in patients who switched at Week 16 from ETN or PBO to APR. During the PBO-controlled period (Weeks 0 to 16), AEs occurring in five percent of patients in any treatment group were diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, headache, and tension headache. During the APR extension phase (Weeks 16–104), AEs that occurred in five percent of patients in any treatment group included those observed during the PBO-controlled period as well as arthralgia, rebound psoriasis, pain in extremity, bronchitis, psoriasis, and sinusitis. Most AEs were mild or moderate in severity, did not increase with prolonged APR exposure, and did not lead to study discontinuation. No clinically meaningful changes were reported in laboratory parameters. No cases of tuberculosis (new or reactivation) were reported during the trial.

Conclusion: In biologic-naive patients with moderate-to-severe psoriasis, improvements in patient-reported outcomes, including QOL and pruritus, were generally maintained with continued APR treatment up to 104 weeks. AEs were consistent with the known safety profile of APR.

Funding/Dislcosures: The authors acknowledge financial support for this study from Celgene Corporation. Joshua Cirulli is an employee of the Celgene Corporation.

A randomized, multicenter, double-blind, placebo-controlled Phase II clinical trial of serlopitant for the treatment of chronic pruritus

A randomized, multicenter, double-blind, placebo-controlled Phase II clinical trial of serlopitant for the treatment of chronic pruritus

Presenters: Ständer S1, Yosipovitch G2, Kerby MB3, Larrick JW4, Perlman AJ4, Schnipper EF4, Zhang X3, Tang JY5, Luger TA2, Steinhoff M6,7

Affiliation: 1Center for Chronic Pruritus, Department of Dermatology, University Hospital Münster, Münster, Germany; 2Miami Itch Center, Department of Dermatology and Cutaneous Surgery Miller School of Medicine, University of Miami, Miami, FL; 3Menlo Therapeutics Inc, Redwood City, CA; 4Velocity Pharmaceutical Development, LLC, San Francisco, CA, USA; 5Department of Clinical Dermatology, Stanford University, Stanford, CA; 6Department of Dermatology and UCD Charles Institute of Translational Dermatology, University College Dublin, Dublin, Ireland; 7Department of Dermatology, University of California San Diego, San Diego, CA

Background/Objective: Chronic pruritus, a common debilitating symptom of many conditions, can result in significant morbidity and impaired quality of life. Inadequate itch relief or undesirable safety and tolerability issues have been associated with many of the current therapies. The neuropeptide substance P and its receptor neurokinin 1 receptor (NK1R) play important roles in pruritus signaling. The potent, highly selective, brain-permeable, oral NK1R antagonist serlopitant is currently under investigation for the treatment of chronic pruritus and other conditions. Here, we report the efficacy and safety results from a Phase II clinical trial of once-daily oral serlopitant versus placebo for the treatment of chronic pruritus (ClinicalTrials.gov ID, NCT01951274).

Methods: Key eligibility criteria included pruritus lasting at least six weeks that was nonresponsive or inadequately responsive to treatment with topical steroids or antihistamines and a baseline Visual Analog Scale (VAS) pruritus score of at least 7cm. Patients were randomized 1:1:1:1 to receive serlopitant 0.25mg, 1mg, 5mg, or placebo. After a loading dose of three tablets at baseline, patients took one tablet daily at bedtime for six weeks. The primary efficacy endpoint was the VAS pruritus score percentage change from baseline. Secondary pruritus measures included the Numeric Rating Scale (NRS), Subject’s Global Assessment of itch, patient responses to the Dermatology Life Quality Index and Pittsburgh Sleep Symptom Questionnaire- Insomnia questionnaires, and the Physician’s Global Assessment. Adverse events (AEs) and clinical and laboratory assessments were evaluated during treatment and follow-up. Change from baseline itch intensity as measured by the VAS and NRS score was analyzed in the intent-to-treat population, and the difference in average change from baseline between the serlopitant and placebo groups was tested using a t-test without control for multiplicity. Primary and secondary efficacy endpoints used an alpha value of p<0.05.

Results: A total of 257 patients were randomized to serlopitant 0.25mg (n=64), 1mg (n=65), or 5mg (n=64) or placebo (n=64); baseline characteristics were comparable between groups. Differences in percentage change from baseline itch VAS score were statistically significantly greater with serlopitant versus placebo for serlopitant 1mg at Weeks 3, 4, 5, and 6 and 5mg at Weeks 4, 5, and 6. Statistically significant improvements in severity of itch from baseline were also demonstrated using the NRS with serlopitant 1mg and 5mg at Weeks 4, 5, and 6 (p?0.05) compared with placebo. The most common treatment-emergent adverse events (TEAEs) in the serlopitant groups were somnolence (1.6%, 4.6%, and 4.7% for serlopitant 0.25mg, 1mg, and 5mg, respectively, and 1.6% for placebo) and diarrhea (0%, 6.2%, and 3.1% for serlopitant 0.25mg, 1mg, and 5mg, respectively, and 1.6% for placebo). Most TEAEs were of mild or moderate intensity. There were no meaningful trends in laboratory abnormalities or changes in vital signs, and no deaths.

Conclusion: Serlopitant 1mg and 5mg provided statistically significant reductions in pruritus intensity compared with placebo. Serlopitant was well tolerated. Almost all TEAEs were of mild or moderate intensity, and no meaningful adverse safety trends were observed in this study.

Burden of axillary hyperhidrosis using a patient-reported outcome measure to assess impact on activities and bothersomeness

Burden of axillary hyperhidrosis using a patient-reported outcome measure to assess impact on activities and bothersomeness

Presenters: Pariser DM1, Hebert AA2, Drew J3, Quiring J4, Glaser DA5

Affiliations: 1Eastern Virginia Medical School and Virginial Clinical Research, Inc., Norfolk, VA; 2UTHealth McGovern Medical School, Houston, TX; 3Dermira, Inc., Menlo Park, CA; 4QST Consultations, Allendale, MI; 5Saint Louis University, St. Louis, MO

Introduction: Hyperhidrosis affects approximately 4.8 percent of the United States population, and approximately three-quarters of patients experience a negative psychological impact. Anxiety and depression are over 3.5 times more common among hyperhidrosis sufferers. The Axillary Hyperhidrosis Patient Measures (AHPM)­—the four-item Axillary Sweating Daily Diary (ASDD), two-item, child-specific version of ASDD [ASDD-C] for patients at least nine years old but less than 16 years old, six Weekly Impact (WI) items, and single-item Patient Global Impression of Change (PGIC)—were developed in consultation with the United States Food and Drug Administration (FDA) and in consideration of FDA patient-reported outcomes (PRO) guidance. Baseline values from two Phase III trials of an investigational axillary hyperhidrosis treatment, topical glycopyrronium tosylate (GT; formerly DRM04), were evaluated to characterize the burden of disease.

Methods: ATMOS 1 (DRM04-HH04, NCT02530281) and ATMOS 2 (DRM04 HH05, NCT02530294) were randomized, double-blind Phase III trials. Patients at least nine years of age with primary axillary hyperhidrosis for at least six months, gravimetrically measured sweat production of at least 50mg per five minutes in each axilla, ASDD axillary sweating severity item (Item 2) 4 or above (numeric rating scale 0 to 10), and Hyperhidrosis Disease Severity Scale (HDSS) Grade 3 or above were randomized 2:1 to GT or vehicle applied once-daily to each axilla for 28 days. Item 1 assessed the presence of underarm sweating and acted as a gatekeeper question for Item 2. ASDD Items 3 and 4 assessed impact and bother of axillary sweating (numeric rating scale 0–4). WI Items assessed the impact of axillary sweating (needing to change shirt during the day, needing to bathe at least once a day, feeling less confident, feeling embarrassed, avoiding interactions, kept from doing an activity on a weekly basis). ASDD items were scored as a weekly average of daily responses. Baseline ASDD item scores and proportion of patients with positive responses to WI items are reported.

Results: Among 697 randomized patients, 665 were at least 16 years of age and were asked Items 3 and 4 and WI items. For ASDD Item 2, 59.3 percent and 59.8 percent of patients had a score of 7 or above (moderately severe sweating) at baseline in ATMOS-1 and ATMOS-2, respectively. For Item 3, 69.4 percent and 71.7 percent had a score of 2 (moderate impact) or above. For Item 4, 77.8 percent and 77.4 percent had a score of 2 (moderate bother) or above. In both studies, a majority of patients reported being impacted by their excess sweating, with most having to avoid interactions or take additional measures (e.g., bathing more than once a day, changing shirts during the day) due to excessive sweating. Over 96 percent of patients experienced embarrassment due to underarm sweating.

Conclusion: In this analysis, over 69 percent and 77 percent of patients reported feeling moderately impacted and bothered by their axillary hyperhidrosis during daily activities at baseline. Nearly all patients (>96%) reported embarrassment, underscoring previously reported negative psychological impact of this underreported and underdiagnosed condition.

Open-label study (ARIDO) evaluating long-term safety of topical glycopyrronium tosylate (GT) in patients with primary axillary hyperhidrosis

Open-label study (ARIDO) evaluating long-term safety of topical glycopyrronium tosylate (GT) in patients with primary axillary hyperhidrosis

Presenters: Glaser DA1, Hebert AA2, Nast A3, Werschler WP4, Shideler S5, Green L6, Mamelok RD7, Drew J8, Quiring J9, Pariser DM10

Affiliations: 1Saint Louis University, St. Louis, MO; 2UTHealth McGovern Medical School, Houston, TX; 3Charité–Universitätsmedizin Berlin, Berlin, Germany; 4Premier Clinical Research, Spokane, WA; 5Shideler Dermatology and Skin Care Center, Carmel, IN; 6George Washington University School of Medicine, Washington, DC; 7Mamelok Consulting, Palo Alto, CA; 8Dermira, Inc., Menlo Park, CA;

9QST Consultations, Allendale, MI; 10Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA

Background/Objective: Hyperhidrosis affects an estimated 4.8 percent of the United States population, or approximately 15.3 million people, and the impact of hyperhidrosis on quality of life is reported as comparable to or greater than psoriasis or eczema. Glycopyrronium tosylate (GT; formerly DRM04) is a topical cholinergic receptor antagonist being developed for the treatment of primary axillary hyperhidrosis in patients nine years of age or older. GT has been assessed in two replicate, randomized, double-blind, vehicle?controlled, pivotal Phase III lead-in trials (ATMOS-1 and ATMOS?2). GT was generally well tolerated and demonstrated clinically meaningful improvements in disease severity and reductions in sweat production through four weeks in these trials. ARIDO (NCT02553798) assessed the long-term safety of GT in a minimum of 100 patients with primary axillary hyperhidrosis treated for at least 12 months.

Methods: ARIDO was a 44-week, open-label extension of ATMOS-1 (NCT02530281) and ATMOS-2 (NCT02530294). In ATMOS-1/ATMOS-2, patients with primary axillary hyperhidrosis were randomized 2:1 to GT (3.75% topical solution) or vehicle applied once daily to each axilla for 28 days (Figure 1). Patients who completed ATMOS-1/ATMOS-2 with at least 80-percent treatment adherence were eligible to continue onto ARIDO and receive open-label GT for up to 44 weeks or until early termination, including patients terminated once the study objective of 100 patients receiving treatment for at least 12 months was achieved. Subjects included in ATMOS-1/ATMOS-2 were at least nine years of age (patients older than 16 were recruited only at US sites), had primary axillary hyperhidrosis for at least six months, showed gravimetrically measured sweat production of at least 50mg per five minutes in each axilla. Included subjects scored a 4 or above on Item 2 (0–10 numeric rating scale) of the Axillary Sweating Daily Diary (ASDD; for patients 16 years of age or older) or ASDD?Children (ASDD-C; for patients under 16 years of age) and 3 or above on the Hyperhidrosis Disease Severity Scale (HDSS). Exclusion criteria included history of a condition that could cause secondary hyperhidrosis; prior surgical procedure or treatment with a medical device for axillary hyperhidrosis, treatment with iontophoresis within four weeks or treatment with botulinum toxin within one year for axillary hyperhidrosis; axillary use of nonprescription antiperspirants within one week or prescription antiperspirants within two weeks; new or modified psychotherapeutic medication regimen within two weeks; treatment with medications having systemic anticholinergic activity, centrally acting alpha-2 adrenergic agonists, or beta-blockers within four weeks (unless dose had been stable for at least four months with no anticipated change); and conditions that could be exacerbated by study medication.

Results: The majority of patients (86.6%; N=564) completing ATMOS-1/ATMOS-2 (369 patients [65.4%] had received GT, and 195 [34.6%] had received vehicle) continued into ARIDO. Of the patients enrolled in ARIDO, most patients were female (55.3%) and Caucasian (83.3%) with a mean age of 33.0 years and mean body mass index (BMI) of 27.3kg/m2. The trial was terminated, per protocol, once study objectives were reached. A total of 226 patients completed 44 weeks of treatment. Through Week 44/ET in ARIDO (up to 48 weeks of GT), GT?treated patients continued to demonstrate improvements in efficacy measures, including sweat production and HDSS responder rate. From baseline in ATMOS-1/ATMOS-2 to Week 44/ET in ARIDO, mean sweat production decreased by 95.7±140.8mg per five minutes, which was maintained from a decrease of 107.6±207.2mg per five minutes in GT?treated patients after four weeks in ATMOS-1/ATMOS-2. At Week 44/ET in ARIDO, HDSS responder rate (?2-grade improvement) was 63.2 percent, a further improvement from 59.1 percent in GT-treated patients at Week 4 in ATMOS-1/ATMOS-2. HDSS grade improved by 1, 2, and 3 grades in 30.9 percent, 46.7 percent, and 16.5 percent of patients, respectively. After 44 weeks, 329 (59.8%) patients reported at least one treatment-emergent adverse event (TEAE), though most were mild or moderate in severity. Most common TEAEs were dry mouth, blurred vision, application site pain, nasopharyngitis, and mydriasis. A total of 44 (8.0%) patients discontinued due to a TEAE and 7 (1.3%) reported at least one serious TEAE. Prespecified anticholinergic TEAEs of interest were reported in 78 (14.2%) patients; most were mild or moderate in severity and were able to be managed by dose interruption. Thirty-seven patients reported 45 vision blurred events; 40 (88.9%) were bilateral. Twenty-nine patients reported 37 mydriasis events; 31 (83.8%) were unilateral.

Conclusion: Safety results were consistent with anticholinergic treatment and with the safety profile observed in prior GT studies, with no new or unexpected findings. Most TEAEs were mild or moderate in severity and considered by the

Investigator to be related to study drug. A low number of subjects discontinued due to a TEAE. While approximately one-third of patients reported local skin reactions, most were mild or moderate in severity. Incidence of TEAEs, including prespecified anticholinergic TEAEs of interest, did not increase with long-term treatment. Efficacy measures obtained at the end of treatment in ARIDO indicated that subjects had maintained sweat production reduction and less bothersome sweating compared with baseline in ATMOS-1/ ATMOS-2. GT was generally well tolerated, and improvements in efficacy measures were maintained in patients with primary axillary hyperhidrosis when applied once-daily to both axillae over a maximum of 48 weeks.

Funding/Disclosures: This study was funded by Dermira, Inc. Medical writing support was provided by Prescott Medical Communications Group (Chicago, IL). Dee Anna Glaser is a consultant and investigator for Dermira, Inc. Adelaide A. Herbert is a consultant for Dermira, Inc. and employee of the University of Texas Medical School, Houston, which received compensation from Dermira, Inc. for study participation. Alexander Nast is an employee of Charité – Universitätsmedizin Berlin, which received compensation from Dermira, Inc. for study participation. William P. Werschler is a consultant and investigator for Dermira, Inc. Stephen Shideler is an investigator for Dermira, Inc. Lawrence Green is a consultant and investigator for Dermira, Inc. and an investigator for Brickell. Richard D. Mamelok is a consultant for Dermira, Inc. Janice Drew is an employee of Dermira, Inc. John Quiring is an employee of QST Consultations. David M. Pariser is a consultant and investigator for Dermira, Inc.