A Message from the Guest Editor and MauiDerm Program Director
The 2018 edition of the MauiDerm for Dermatologists meeting had a wide variety of clinical and scientific data presented not only at the podium, but in its poster sessions as well. A wide range of clinically relevant material was presented in poster format. For those of you who were not on hand ro review the posters and discuss them with their authors, we have compiled and indexed selected posters from the 2018 meeting. It is my hope that you will find the posters informative and thought provoking.
For an alphabetical index organized by poster author, please see page 31 of this supplement.
George Martin, MD
MauiDerm 2018 Program Director; Guest Editor, the Journal of Clinical and Aesthetic Dermatology
J Clin Aesthet Dermatol. 2018;11(5 Suppl):S8–S30
An open-label study evaluating the quality of life, long-term efficacy, and safety of lidose-isotretinoin (ABSORICA®) capsules administered without food in patients with severe recalcitrant nodular acne: interim analysis of 20-week active treatment period
Presenters: Zaenglein A1, Del Rosso J2
Affiliations: 1Department of Dermatology, Pennsylvania State University, Hershey, PA; 2JDR Dermatology Research/Thomas Dermatology, Las Vegas, NV
Background/Objective: Severe acne is known to have a significant adverse effect on self-esteem and quality of life (QoL). Effective treatment of acne with isotretinoin can subsequently improve the patient’s QoL. The timing of QoL improvement over the course of treatment with lidose-isotretinoin has not been established. Isotretinoin products must be taken with a high-fat meal to achieve optimal absorption. Fasted plasma levels of isotretinoin can be nearly 60-percent lower than fed levels. Nonadherence with the food intake requirements can potentially compromise the long-term efficacy of isotretinoin. Absorption of lidose-isotretinoin is less dependent on the amount and/or type of food intake, and it can be taken without meals while still providing a reliable isotretinoin blood concentration. In this study, we evaluated the efficacy and safety of lidose-isotretinoin taken without food by patients with severe recalcitrant nodular acne, as well as assessed their quality of life. Primary objective during the 20-week active treatment period (ATP) was to evaluate the QoL of patients taking lidose-isotretinoin twice daily (bid) without food. Secondary objectives during the ATP were to evaluate the efficacy and safety of lidose-isotretinoin taken twice-daily without food.
Methods: This was a Phase IV, multicenter, single-arm, open-label study conducted in the United States in patients with severe recalcitrant nodular acne (NCT02457520) consisting of two phases: a 20-week (5-month) open-label ATP and a 104-week post-treatment period. Patients were included in the study if they were 12 to 45 years of age with recalcitrant acne severe enough for isotretinoin treatment, including five or more facial nodules. Included patients had no prior exposure to systemic isotretinoin or other systemic retinoid and weighed between 40kg and 110kg. Women included in the study could not be pregnant or breastfeeding; women of childbearing potential had to use two forms of effective contraception simultaneously for one month before the trial, during the trial, and for one month after stopping study medication, or commit to continuous abstinence from heterosexual intercourse.
Dosing during the 20-week ATP to attain target cumulative dose of 120mg to 150mg per kilogram of weight was 0.5mg/kg per day divided into two daily doses for four weeks, followed by 1.0 mg/kg per day divided into two daily doses for 16 weeks. Study medication was taken without food (1 hour before or at least 2 hours after ingestion of food or beverages other than water). Primary efficacy endpoint was the change from baseline to the end of treatment (EOT) in the Acne-QoL score, assessed on a graded scale (overall and by domain). Domains included self-perception, role-social, role-emotional, and acne symptoms. Secondary efficacy endpoints included monthly change from baseline in Acne-QoL scores (overall and by domain) and lesion counts during the ATP and change from baseline to EOT in Investigator’s Global Assessment (IGA) scores. Efficacy evaluation was conducted using the intent-to-treat (ITT) population. Overall Acne-QoL score, each domain score, and the changes from baseline for these scores were summarized using descriptive statistics. Differences between baseline and postbaseline values were analyzed using paired t-tests. Descriptive statistics are provided for mean percentage change from baseline value for inflammatory, noninflammatory, and total lesion counts. Differences between baseline and postbaseline values were analyzed using paired t-tests. Descriptive statistics are provided for IGA observed values.
Results: A total of 201 patients (mean age: 18.7 [range: 12–45] years) were enrolled in the study at 21 sites. Eighty-five percent (n=170/201) of patients completed the 20-week ATP. There was a significant increase in standard deviation (SD) Acne-QoL from baseline to EOT (61.4 [28.4] vs. 99.0 [19.8], P<0.0001). All four domains (self-perception, role-social, role-emotional, acne symptoms) were significantly improved over the course of treatment, with positive improvements beginning at Week 4. Mean (SD) percentage change in inflammatory (-87.2 [22.5]) and noninflammatory lesion (-83.2 [30.3]) counts from baseline to EOT were significant (P<0.0001).
Mean IGA scores improved from baseline by approximately 3.0 points at EOT. A total of 286 adverse events (AEs) was reported in 60.2 percent of patients (121/201). The most common AEs were dry skin (10.9%), dry lips (10.4%), and cheilitis (9.0%)
A total of 166 treatment-related AEs was reported in 46.3 percent of patients (93/201). Twelve severe AEs were reported; five were considered to be treatment-related (nausea [n=2], increased blood cholesterol [n=1], liver function test abnormal [n=1], and headache [n=1]). Psychiatric AEs occurred in 17 patients (8.5%). The psychiatric events reported were depression (4.0%), insomnia (1.0%), and anxiety (1.0%). Abnormal laboratory results occurred in 11 patients (5.5%), including increases in blood triglycerides (3.5%), alanine aminotransferase (1.5%), aspartate aminotransferase (1.5%), and blood cholesterol (1.5%). One serious AE was reported: diabetes mellitus on Study Day 127, severe in intensity and unlikely related to study treatment. Eight patients discontinued the study due to AE (psychiatric events [n=5] and abnormalities in laboratory test results [n=3]). Six additional patients had study drug withdrawn for an AE (psychiatric events [n=4], migraine [n=1], and diabetes mellitus [n=1]).
Conclusion: Twice-daily use of lidose-containing isotretinoin taken without food improved QoL over the 20-week treatment period, with improvement seen as early as Week 4. Clinical efficacy was also demonstrated. AEs were generally consistent with the known safety profile for isotretinoin.
Funding/Disclosures: This study was funded by Sun Pharmaceutical Industries, Inc. Andrea Zaenglein has served as a consultant for Ranbaxy/Sun Pharmaceutical Industries, Inc. James Del Rosso has served as a consultant, speaker, and research investigator for Sun Pharmaceutical Industries, Inc.
Adapalene 0.3% / benzoyl peroxide 2.5% gel plus oral doxycycline is an effective and safe option for oral isotretinoin candidates with severe inflammatory acne (non-nodulocystic/nonconglobate)
Presenters: Del Rosso J1, Gold LS2, Johnson SM3, Rueda MJ4, Baldwin H5, Lain EL6, Landis M7, Rendon M8, Tanghetti E9, Thiboutot D10, Weiss J11
Affiliations: 1Thomas Dermatology, Las Vegas, N; 2Henry Ford Medical Center, Deptartment of Dermatology, Detroit, MI; 3Johnson Dermatology, Fort Smith, AR; 4Galderma Laboratories, L.P., Fort Worth, TX; 5The Acne Treatment and Research Center, Morristown, NJ; 6Austin Institute for Clinical Research, Pflugerville, TX; 7Forefront Dermatology, Jeffersonville, IN; 8Rendon Center for Dermatology and Aesthetic Medicine, Boca Raton, FL; 9Center for Dermatology and Laser Surgery, Sacramento, CA; 10The Pennsylvania State University College of Medicine, Hershey, PA; 11Gwinnett Dermatology, Snellville, GA
Background/Objective: Acne treatment guidelines suggest combined topical therapy with oral antibiotics or oral isotretinoin (OI) as first-line treatments for severe acne. This study tested the efficacy and safety of a daily regimen of 0.3% adapalene/benzoyl peroxide (ABPO) gel and oral doxycycline 200mg (DOX, two 50mg delayed-release tablets twice-daily) in severe (non-nodulocystic, nonconglobate) inflammatory acne.
Methods: This was a Phase IV, 12-week, single-arm, open-label, multicenter investigational study. Men and women aged 12 years or older with severe inflammatory acne (IGA 4, n=186) and considered OI candidates by the investigator were enrolled. OI candidacy was reevaluated at each study visit. Efficacy endpoints included inflammatory lesion (IL) reduction (Week 12), IGA success (Weeks 4, 8, and 12), percent-reduction in lesions (Weeks 4, 8, and 12), and subject questionnaires (Week 12). Safety assessments included adverse events (AEs) and tolerability.
Results: Mean IL counts were significantly reduced (standard deviation [SD]; baseline, 44.8 (21.73); Week 12, 14.8 (16.11); mean percent-reduction, 66.2% [30.47]; P<.0001). By Week 12, 37.1 percent of subjects achieved IGA Success (n=69, P<0.0001). Most subjects self-reported at least moderate improvement in acne (90.2%) and were “Satisfied” or “Very Satisfied” with the study treatment overall (83.2%). Nearly half (41.9%) of the subjects were no longer considered OI candidates at Week 4. At 12 weeks, just 19.9 percent were still considered OI candidates. Twenty-seven (15.4%) AE were considered to have a reasonable possibility of being treatment-related (gastrointestinal disorders were the most common; n=7, 4.0%). Only four subjects discontinued due to an adverse event, (“skin burning sensation”; 1 mild, 2 moderate, 1 severe; all were considered “possibly related”).
Conclusion: 0.3% A/BPO plus DOX is an effective and safe treatment option for severe inflammatory acne (non-nodulocystic, nonconglobate) before starting OI treatment or as an alternative when OI cannot be used.
Funding/disclosures: This study was sponsored by Galderma Laboratories, L.P. Galderma is the maker of Epiduo Forte Gel. Dr. Rueda is an employee of Galderma. All other authors are advisors or investigators for Galderma.
IncobotulinumtoxinA versus onabotulinumtoxinA in the treatment of glabellar facial lines: results from a multicenter, randomized, double-blinded trial
Presenters: Kane MAC1, Gold MH2, Coleman WP III3, Jones DH4, Tanghetti EA5, Alster TS6, Rohrer TE7, Burgess CM8, Shamban AT9
Affiliations: 1Manhattan Eye, Ear & Throat Hospital, New York, NY; 2Tennessee Clinical Research Center, Nashville, TN; 3Tulane Health Sciences Center, New Orleans, LA; 4Skin Care and Laser Physicians of Beverly Hills, Los Angeles, CA; 5Center for Dermatology and Laser Surgery, Sacramento, CA; 6Washington Institute of Dermatologic Laser Surgery, Georgetown University Hospital, Washington, DC; 7Skin Care Physicians, Chestnut Hill, MA; 8Center for Dermatology and Dermatologic Surgery, Washington, DC; 9University of California Los Angeles, Los Angeles, CA
Background/Objective: Botulinum toxin type A is a well-established treatment for glabellar frown lines. Head-to-head comparison studies have demonstrated that incobotulinumtoxinA (Xeomin®) versus onabotulinumtoxinA (Botox®) result in comparable safety and efficacy for both cosmetic and therapeutic uses. In 2011, incobotulinumtoxinA was approved by the United States Food and Drug Administration (FDA) for improvement in the appearance of moderate-to-severe glabellar frown lines with a recommended dosage of 20 units (U).
This is the first large, multicenter, randomized, double-blinded, parallel-group study to compare the efficacy and safety of incobotulinumtoxinA versus onabotulinumtoxinA after a single 20U treatment to improve the appearance of glabellar frown lines.
Primary endpoint was response defined as a 1-point or greater improvement from baseline on the Facial Wrinkle Scale (FWS) at maximum frown one month from treatment.
Methods: Patients were randomized 1:1. Two-hundred and fifty female subjects 18 to 50 years of age (median age was 41 for both groups) with moderate-to-severe GFL on a 4-point FWS at maximum frown were included. Study duration was 120 days for each subject, plus the individual duration of screening (Day ?14 to 0). Eligible subjects received a single injection of the study treatment at Day 0 (baseline). Dose was 20U in both treatment groups; injection volume was 0.5mL.
Results: Primary endpoint was met. Primary efficacy analysis demonstrated equivalence of incobotulinumtoxinA and onabotulinumtoxinA at one month, with 95.7 percent of subjects in the incobotulinumtoxinA group achieving at least a 1-point improvement on FWS and 99.2 percent of subject in that onabotulinumtoxinA group achieving the same. Treatment satisfaction for both groups remained above 90 percent for the entire four-month treatment period. Fourteen (11.5%) subjects treated with incobotulinumtoxinA reported treatment-emergent adverse events (TEAE); 18 (14.1%) of subjects in the onabotulinumtoxinA group reported TEAEs. The most common TEAE among both groups was headache (incobotulinumtoxinA: n=7; onabotulinumtoxinA: n=5).
Conclusion: IncobotulinumtoxinA and onabotulinumtoxinA result in similar efficacy and safety profiles for the treatment of glabellar facial lines.
Funding: This study was funded by Merz North America, Inc.
Microfocused ultrasound in combination with diluted calcium hydroxylapatite for improving skin laxity and the appearance of lines in the neck and décolletage
Presenter: Casabona G
Affiliation: Cosmetic and Surgical Dermatology and Mohs Surgery, Clinica Vida, Sao Paulo, Brazil
Background/Objective: Skin laxity and wrinkling on the neck and décolletage can be age-revealing. The objective of this study was to evaluate the combined use of microfocused ultrasound with visualization (MFU-V) and diluted calcium hydroxylapatite (CaHA) for treating lines and wrinkles of the neck and décolletage.
Methods: Subjects with moderate-to-severe lines on the neck and/or décolletage were retrospectively enrolled. Prior to MFU-V treatment, a topical anesthetic (7% lidocaine, 7% prilocaine) was applied. For both the neck and décolletage, subjects were treated at two depths using the 7MHz transducer at a focal depth of 3.0mm and the 10MHz transducer at a depth of 1.5mm, applying 150 lines for each transducer per site. Immediately after MFU-V, subjects received treatment with CaHA (1.5 ml diluted 1:1 with 1.5 ml of 2% lidocaine solution). For the neck, CaHA was injected subdermally in microdroplets using a fanning technique with a 25G long cannula from four points of entrance starting on top of the lines and extending in a fan shape around the lines to cover the same area as the MFU-V (half a syringe per side). A similar technique was used for décolletage, but with three points of entry. Injections were followed by vigorous massage to ensure that the product was evenly dispersed. Subjects were assessed for skin laxity and wrinkling in the neck and décolletage at baseline and at 90 days (2 blinded, independent evaluators) using three validated scales: Merz Aesthetics Décolleté Scale and Fabi-Bolton Chest Wrinkle Scale (both scales range from 0=no wrinkles, 1=mild wrinkles, 2=moderate wrinkles, 3=severe wrinkles 4=very severe wrinkles); and Allergan Transverse Neck Lines Scale (ranging from 1=no wrinkles to 5=very severe wrinkles. Subject satisfaction was assessed using a 5-point scale (1=very unsatisfied, 2=unsatisfied, 3=neither satisfied nor dissatisfied, 4=satisfied, 5=very satisfied). Pain was assessed and adverse events (AEs) were documented.
Results: At baseline, 24 out of the 42 subjects were given a Grade 2 in the Allergan Transverse Neck Line Scale by Evaluator 1; Evaluator 2 placed 23 out of 42 subjects in the Grade 2 category. None of the subjects achieved a Grade 1 for neck lines at baseline. At 90 days, Evaluators 1 and 2 placed 30 and 27 subjects, respectively, in the Grade 1 category for neck lines. At baseline, 17 out of 18 subjects and 16 out of 18 subjects were given a Grade 2 or higher on the Merz Aesthetics décolletage wrinkles scale. At 90 days, 18 out of 18 subjects achieved a Grade 2 or lower from both evaluators. Using the subject satisfaction scale at baseline, the majority (64.3%) were neither satisfied nor dissatisfied with the neck lines treatment. At Month 3, the majority (54.8%) were very satisfied with the neck lines treatment. At baseline, the majority (66.7%) were neither satisfied nor dissatisfied with the décolletage treatment. At Month 3, 50.0 percent were satisfied and 44.4 were very satisfied with the décolletage treatment. Mild pain was experienced by 90 percent of subjects during the procedure; 10 percent reported no discomfort at all. All subjects experienced bruising, which resolved in three to seven days. No other AEs were reported.
Conclusion: Combining MFU-V with 1:1 diluted CaHA is effective in improving the appearance of neck and décolletage lines and wrinkles. Both procedures were well tolerated, and subject satisfaction was high.
Differential facial aesthetic treatment considerations for skin of color populations: African American, Asian and Hispanic
Presenters: Boyd C1, Chiu A2, Montes JR3, Narurkar V4; Shumate GT5, Gallagher CJ5
Affiliations: 1BOYD, Birmingham, MI; 2The Derm Institute, Hermosa Beach, CA; 3José Raúl Montes Eyes & Facial Rejuvenation, San Juan, PR; 4Bay Area Laser Institute, San Francisco, CA; 5Allergan plc, Irvine, CA
Background/Objective: By 2050, more than half of the total population in the United States will be of African American, Asian, or Hispanic descent. The unique anatomical needs, aesthetic goals, and cultural considerations for these growing patient populations should be evaluated to optimize treatment expectations and outcomes. A research study was performed to gain insights into the areas of aesthetic concern, relative prioritization of treatment areas, and any barriers to receiving injectables among these populations.
Methods: Four-hundred and one African American, 403 Asian, and 401 Hispanic women living in the United States, aged 30 to 65 years, completed an online evaluation in which questions focused on identifying bothersome facial areas, consideration levels for facial aesthetic treatments, and any barriers to receiving injectables. A maximum difference scaling method was used to identify which of the 15 facial areas would be prioritized for treatment. Respondents were naïve to facial aesthetic treatments but were aesthetically oriented and were considering physician administered aesthetic treatment within the next two years.
Results: The Hispanic population reported the highest consideration rate for injectables (85%), followed by Asian (75%) and African Americans (64%). African American and Hispanics were most bothered by their submental region, whereas Asian respondents were most bothered by the area underneath the eyes (infraorbital area). All skin of color populations prioritized first the periorbital region (infraorbital and crow’s feet areas) followed by the submental area and forehead lines. Relative to the other populations, African American respondents expressed the highest prioritization of the submental region. All respondents then prioritized treatment of glabellar lines, nasolabial folds, and oral commissures. Analysis by increasing Fitzpatrick Type (I–VI) showed an increasing prioritization of the periorbital region and decreasing prioritization of the chin and perioral lines. Most frequently cited barriers to considering injectable treatment included safety and side effects, concern about injecting a foreign substance into the body, and cost.
Conclusion: Understanding the unique aesthetic considerations of a diversifying patient population is imperative. Differences in injectable consideration rates and bothersome areas were apparent across the patient populations evaluated, but there was consensus regarding the facial areas most likely to be prioritized for treatment. An understanding of the differential aging patterns, cultural considerations, and aesthetic goals for each patient population may help optimize treatment expectations and outcomes.
Subject satisfaction demonstrated for two on-label injection volumes of abobotulinumtoxinA (ABO) when used to treat moderate-to-severe glabellar lines
Presenters: Cohen J1, Kaufman J2, Peredo M3, Jonas B4, Nogueira A4, Mashburn J4
Affiliations: 1Director of AboutSkin Dermatology and DermSurgery, Greenwood Village and Lone Tree, CO, Associate Clinical Professor, Department of Dermatology, University of Colorado, CO, and Assistant Clinical Professor, Department of Dermatology, University of California Irvine; 2Skin Associates of South Florida, Skin Research Institute, Coral Gables, FL; 3Marina I. Peredo, MD, Smithtown, NY; 4Galderma Laboratories, L.P., Fort Worth, TX
Background/Objective: In the United States (US), glabellar lines (GLs) are most often treated with botulinumtoxin type A (BoNT-A), and satisfaction with treatment is typically measured using patient-reported outcomes. Dysport (abobotulinumtoxinA [ABO]) is approved in the United States for the treatment of GLs and can be injected at two different injection volumes—0.05mL and 0.08mL. This was a multicenter, randomized, subject- and evaluator-blinded study to evaluate the safety, efficacy, and subject satisfaction of two on-label injection volumes, 0.05mL/injection (Group A) and 0.08mL/injection (Group B), for the treatment of GLs. This report focuses on the subject satisfaction health-related quality of life aspects of the study.
Methods: Subjects with moderate-to-severe GLs at maximum frown were treated with ABO. Subjects were randomized to receive either 0.05mL/injection (Group A) or 0.08mL/injection (Group B), per the approved US label (5 injection points in the glabella area totaling 50U [10U at each injection site] for 1 treatment session). Subjects were given one treatment, then followed for up to four months. Subject assessments were completed before and after treatment.
Results: At 30 days posttreatment, the majority of subjects reported they were satisfied with how attractive they looked (86.7% for Group A, 76.7% for Group B), compared to baseline pretreatment, 20.0 and 36.7 percent, respectively. Subjects also felt more confident after either treatment (90.0% and 80.0% at Day 30, Group A and B, respectively) compared to baseline, 33.3 and 33.3 percent, respectively. At Day 30, subjects also reported an increase in psychological well-being (mean change from baseline 29.5 [P<0.0001] for Group A and 25.0 [P<0.0001] for Group B), being less bothered by their GLs (mean change from baseline 52.2 [P<0.0001] for Group A and 45.7 [P<.0001] for Group B), and looking four years younger than their current age compared to baseline (mean change from baseline -4.4 [P<0.0001] for Group A and -4.3 [P<0.0001] for Group B). These results were mostly maintained through 120 days posttreatment. There were no significant differences between treatment groups.
Conclusion: Subjects treated with two on-label injection volumes of ABO for moderate-to-severe GLs reported high subject satisfaction and increased psychological well-being through Day 120.
Funding: Galderma Laboratories, L.P.
Reduction of submental fat continues beyond 28 days after ATX-101 treatment: results from a post-hoc analysis
Presenters: Dover JS1, Shridharani SM2, Bloom JD3, Somogyi C4, Gallagher CJ4
Affiliations: 1SkinCare Physicians, Chestnut Hill, MA; 2LUXURGERY, New York, NY; 3Main Line Center for Laser Surgery, Ardmore, PA; 4Allergan plc, Irvine, CA
Background/Objective: ATX-101 (deoxycholic acid injection) is approved in the United States, Australia, Canada, and Europe for reduction of submental fat (SMF). When injected into subcutaneous fat, ATX-101 results in adipocytolysis, which induces a localized inflammatory response to clear cellular debris and lipids liberated from the injection site. In ATX-101 clinical trials, subjects received 4 to 6 treatments spaced at intervals of 28 ± 5 days. A post-hoc analysis was conducted to characterize the response after a single ATX-101 treatment using data from a patient experience management study (NCT02007434).
Methods: Adults aged 18 to 65 years with a moderate or large amount of SMF (as assessed via the validated 5-point Clinician-Reported and Patient-Reported SMF Rating Scales) who were dissatisfied with the appearance of their face or chin were enrolled. Subjects were randomized to one treatment with either ATX-101 (area-adjusted dose: 2mg/cm2) or placebo. This post-hoc analysis evaluated efficacy among ATX-101-treated subjects (n=68); subjects with moderate SMF at baseline based on clinician assessment (n=49) received 6mL of ATX-101 while subjects with severe SMF (n=19) received 8mL. Outcomes, evaluated at Days 28 and 84 following ATX-101 treatment, included the percentage of subjects who achieved at least a 1-grade improvement in SMF from baseline based on clinician assessment (CR-1 response), percentage of subjects who achieved at least 1-grade improvement in SMF from baseline based on clinician and subject assessment (composite CR-1/PR-1 response), and mean change in SMF thickness from baseline (measured with calipers).
Results: Most ATX-101-treated subjects were female (62%) and Caucasian (79%). At baseline, 72 percent versus 28 percent of subjects had a moderate versus large amount of SMF, respectively. At Day 28, the CR-1 response rate was 14.1 percent. By Day 84, the CR-1 response rate increased to 47.0 percent. Similarly, the composite CR-1/PR-1 response rate was 7.8 percent at Day 28, and increased to 37.9 percent by Day 84. SMF thickness increased from baseline by 2.1mm at Day 28, which might be related to residual swelling and/or induration within the treatment area. However, SMF thickness decreased from baseline by 1.3mm at Day 84.
Conclusion: Results from this analysis demonstrate that reduction of SMF continues in 2 to 3 months following ATX-101 treatment. Overall, these data provide evidence of a progressive reduction in SMF beyond the 28-day retreatment interval used in the pivotal clinical trials and suggest that benefit might be gained by extending the interval between ATX-101 treatments beyond 28 days.
Funding: Funded by Allergan plc.
Efficacy, safety, and patient-reported outcomes following onabotulinumtoxinA treatment for moderate-to-severe forehead lines: a pooled analysis of two Phase III pivotal trials
Presenters: De Boulle K1, Fagien S2, Mao C3, Shumate GT3, Gallagher CJ3
Affiliations: 1Aalst Dermatology Clinic, Aalst, Belgium; 2Aesthetic Eyelid Plastic Surgery, Boca Raton, FL; 3Allergan plc, Irvine, CA
Background/Objective: Two pivotal, Phase III studies were conducted to evaluate the safety and efficacy of onabotulinumtoxinA (onabotA) versus placebo (PBO) for treatment of moderate-to-severe forehead lines (FHL).
Methods: In both studies, neurotoxin-naïve subjects were randomized to receive onabotA 40U (frontalis 20U, glabella 20U) or PBO. The second study included an additional treatment arm in which bilateral crow’s feet regions (CFL) were also treated for a total dose of 64U (FHL 20U, GL 20U, CFL 24U) or PBO. After Day 180, all eligible subjects could receive up to two additional open-label onabotA treatments, with assessments to Day 360. Dynamic and static FHL were assessed at all timepoints by both investigator and subject using the Facial Wrinkle Scale with photo numeric guide. Subject satisfaction with treatment was evaluated using the validated Facial Lines Satisfaction Questionnaire (FLSQ).
Results: This pooled analysis comprised 1,178 subjects in the intent-to-treat (ITT) population (onabotA 40U n=608, onabotA 64U n=313; PBO n=257). At maximum eyebrow elevation, Day 30 responder rates for those achieving more than a 2-grade composite FHL improvement based on investigator and subject FWS were 53.1 (40U) and 53.0 (64U) percent, respectively. Responder rates for those achieving more than a 1-grade FHL improvement were 97.9 (40U) and 99.0 (64U) percent, respectively. Percentage of subjects achieving a score of none/mild FHL were 92.3 (40U) and 94.9 (64U) percent, respectively. Of those subjects with at least mild static FHL at baseline, 85.4 (40U) and 84.8 (64U) percent achieved more than a 1-grade improvement at rest. Efficacy and patient satisfaction were comparable across treatment cycles. Based on the FLSQ, 85.6 (40U) and 87.9 (64U) percent of subjects reported being mostly satisfied or very satisfied with the effect treatment had on their forehead lines at Day 60. Across all treatment cycles over 12 months, 25.4 percent of subjects had treatment-related adverse events; of note were brow ptosis (2.6%) and lid ptosis (1.8%). Most frequently reported treatment-emergent adverse events included headache (11.8%), injection site bruising (7.4%), nasopharyngitis (8.3%), and upper respiratory tract infection (4.3%). No new safety signals were detected with repeated upper facial line treatments.
Conclusion: OnabotA significantly improved the appearance of FHL. Treatment of upper facial lines was well tolerated with efficacy and patient satisfaction maintained across repeat treatments.
Understanding the African American facial aesthetic patient
Presenters: Boyd C1, Alexis A2, Callender V3, Downie J4, Shumate GT5, Gallagher CJ5
Affiliations: 1BOYD, Birmingham, MI; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3Callender Dermatology and Cosmetic Center, Glenn Dale, MD; 4Image Dermatology, Montclair, NJ; 5Allergan plc, Irvine, CA
Background/Objective: Aesthetic injectors might perceive challenges when addressing the aesthetic needs of African American patients. Understanding the anatomical considerations, facial aging patterns, aesthetic concerns, and treatment preferences might increase the comfort level for the injector and improve outcomes for African American patients. Injectors should also consider any patient misconceptions (e.g., keloid scarring) associated with injection procedures. Accordingly, clinical case studies can provide practical examples of how to implement this knowledge during patient consultation, assessment, and treatment. Two studies were performed to gain insights into self-reported facial aging characteristics and treatment considerations among African American patients.
Methods: Eight-hundred and fifty-nine African American men (145) and women (714) completed an online evaluation in which they assessed their facial features against photonumeric scales depicting degrees of severity for 10 facial characteristics. Four-hundred and one African American women completed a separate online evaluation to identify areas of aesthetic concern, relative prioritization of treatment areas, and attitudes toward injectable treatments. Respondents for both evaluations were naïve to facial aesthetic treatments. A subsequent meeting of experts with significant experience in treating African American patients produced case studies to illustrate the translation of these data to the clinical setting.
Results: In the African American population, moderate-to-severe signs of facial aging were not generally reported until 50 to 79 years of age. At ages 70 to 79 years, over 70 percent were still without moderate-to-severe perioral lines, loss of lip fullness, or midface volume loss. The majority reported having uneven skin tone/color (57%) and dark circles under the eyes (48%). African American patients were most bothered by their tear trough and submental regions. Areas most likely to be prioritized for treatment included tear trough, submental region, and horizontal forehead lines. In contrast, African American patients were less likely to prioritize treatment of perioral lines, lips, temples, and cheeks. African American women reported the lowest consideration rate for injectables (64%), compared to Asian or Hispanic individuals. “Looking good for their age” was the top reason for considering aesthetic treatment, but the cost, perceived safety, and side effects were the largest barriers. Clinical case studies demonstrated practical treatment strategies utilizing commercially available facial aesthetic products.
Conclusion: Across the two research studies, self-reported facial aging characteristics correlated with bothersome areas; both tear trough treatment and submental fat reduction could be seen as entry points for facial aesthetic injectables for this population. An understanding of these objective research findings and practical case studies might increase the comfort level for an injector and improve outcomes for African American patients.
Clinical efficacy and tolerability of a hydroquinone-free and retinol-free topical brightening serum on females with facial melasma
Presenters: Makino ET, Tan P; Mehta RC
Affiliation: Research & Development SkinMedica, an Allergan Company, Irvine, CA
Background/Objective: Melasma, a progressive form of hyperpigmentation, occurs more often in healthy women than men. The actual etiology is indefinite; however, pregnancy, hormonal changes, ultraviolet (UV) light exposure, photosensitizing medications, and genetic predisposition have all been considered as contributing factors. This dysfunction of the pigmentary system results in symmetric brown or gray-brown patches on sun exposed areas of the face, particularly on the forehead, cheeks, upper lip, and chin. Often, the psychosocial impact of melasma leads to a negative effect on quality of life and emotional well-being. The purpose of this study was to assess the cosmetic efficacy and tolerability of a HQ-free and retinol-free serum (LYT2) in nonpregnant women with mild-to-severe melasma that was self-perceived as being induced by a previous pregnancy.
Methods: This was a 12-week, single-center, clinical usage study with visits at baseline and Weeks 4, 8 and 12. Thirty female subjects aged 30 to 50 years with Fitzpatrick Skin Types (FST) II to IV presenting with mild-to-severe overall hyperpigmentation on the face due to melasma, which was self-perceived to be induced by a previous pregnancy, completed the study. Seventy-three percent of the subjects were Caucasian, 20 percent were Asian, and seven percent were African American. All subjects received LYT2, cleanser, moisturizer, and sunscreen. Subjects applied LYT2 twice-daily after cleansing. All subjects used cleanser and moisturizer twice-daily and a physical sunscreen once in the morning (and as needed throughout the day). At all visits, the investigator assessed for overall hyperpigmentation (0–9 scale; 0=none, 1–3=mild, 4–6=moderate, 7–9=severe), global Improvement in Overall Hyperpigmentation (0–5 scale), and Melasma Area and Severity Index (MASI). Each subject’s face was divided into four areas that were evaluated separately (forehead [F], right malar region [MR], left malar region [ML], and chin [C]). For each area, the pigment intensity (PI), lesion size (A), and homogeneity (H) were assessed. MASI score for the whole face was calculated using the following equation: MASI=0.3 (PIF + HF) AF + 0.3 (PIMR + HMR) AMR + 0.3 (PIML+ HML) AML + 0.1 (PIC + HC) AC. The values 0.3, 0.3, 0.3, and 0.1 represent the respective percentages of total facial area. The maximum score for MASI is 48 and the minimum score is 0. Tolerability assessments for erythema, scaling, edema, burning, stinging, and itching were graded on a 4-point scale at all visits. At all follow-up visits, subjects completed a self-assessment questionnaire on self- perceived efficacy, product texture, and product attributes. At baseline and Week 12, subjects completed a Melasma Quality of Life (MelasQol) Questionnaire (Likert Scale: 1=not bothered at all to 7=bothered all the time).Standardized digital photographs were taken using the VISIA-CR Imaging System (Canfield Imaging Systems) at all visits. Image analysis on a target dark spot for skin brightness (L*) was conducted for each time point. Corneometer and tewameter measurements were conducted for all visits.
Results: The HQ-free and retinol-free serum demonstrated a statistically significant decrease in clinical grading scores at Weeks 4, 8, and 12 when compared with baseline for overall hyperpigmentation, global improvement in overall hyperpigmentation, and MASI (all p<0.001; Wilcoxon Signed-Rank Test). Statistically significant increase in mean scores for global improvement in overall hyperpigmentation at all visits (all p<0.001; Wilcoxon Signed-Rank Test). MelasQol Combined Score showed a statistically significant improvement at Week 12 compared to baseline, indicating an increased perception of quality of life (p<0.03; Wilcoxon signed-rank test). Corneometer and tewameter measurements continuously improved from baseline at all follow-up visits, indicating an improvement in skin hydration and skin barrier function, respectively. Image analysis for brightness (L*) showed statistically significant improvements from baseline at all follow up visits (all p?0.025; paired t-test). LYT2 was well tolerated with tolerability scores remaining similar to baseline scores, and highly rated by subjects for self-perceived efficacy and product attributes with a significant proportion of subjects agreeing to favorable responses by Week 12. Ninety-seven percent of subjects were satisfied with LYT2 by Week 12. Seventy-seven percent of subjects saw moderate or marked improvement by Week 12. Eighty-three percent of subjects agreed it performed better than past facial treatments.
Conclusion: Results from this study support the efficacy and tolerability of this HQ-free and retinol-free serum in improving the appearance of mild-to-severe facial melasma in subjects with self-perceived pregnancy-induced melasma.
Funding/Disclosures: This study was sponsored by Allergan. All authors met the ICMJE authorship criteria. All authors are employees of Allergan.
A Phase IIb dose-ranging efficacy and safety study of tralokinumab in adult patients with moderate-to-severe atopic dermatitis (AD)
Presenters: Wollenberg A1, Howell MD2, Guttman-Yassky E3, Silverberg JI4, Birrell C5, Kell C5, Ranade K2, Dawson M5, van der Merwe R5
Affiliations: 1Ludwig Maximillian University, Munich, Germany; 2MedImmune, LLC, MD; 3Mount Sinai School of Medicine, NY; 4Northwestern University Feinberg School of Medicine, IL; 5MedImmune, Ltd., Cambridge, UK
Background/Objective: AD is a chronic inflammatory skin disease characterized by increased interleukin (IL)-13 levels. Tralokinumab, an anti-IL-13 monoclonal antibody, has shown efficacy and an acceptable safety profile in patients with severe, uncontrolled asthma driven by the T-helper 2 pathway. Serum dipeptidyl peptidase 4 (DPP-4) has been reported as a predictive marker for tralokinumab in patients with severe asthma. Here, we evaluated whether tralokinumab offers therapeutic benefit to adults with moderate-to-severe AD.
Methods: In this Phase IIb, randomized, placebo-controlled, double-blind study (NCT02347176), patients were randomized 1:1:1:1 to receive tralokinumab 45mg, 150mg, or 300mg, or placebo every two weeks with mid-strength topical corticosteroids (TCS) for 12 weeks. Coprimary endpoints were change from baseline in Eczema Area Severity Index (EASI) and percentage of patients with clear or almost clear Investigator’s Global Assessment (IGA 0/1) at Week 12. Further efficacy, patient-reported outcomes, serum biomarkers, and safety endpoints were assessed.
Results: Overall, 204 patients were randomized. Tralokinumab 300mg treatment significantly reduced EASI scores (adjusted mean [standard error] change from baseline: 15.7 [1.3]; p=0.011) vs. placebo (-10.8 [1.4]) and more patients had IGA 0/1 (26% vs. 12%). Significant improvements were observed in patients who received tralokinumab 300mg versus placebo for Scoring of Atopic Dermatitis (p=0.002), Dermatology Life Quality Index (p=0.006), Pruritus Numeric Rating Scale (p=0.002), EASI75 (p=0.003), and EASI50 (p=0.025). Tralokinumab 300mg significantly reduced the number of Staphylococcus aureus-colonized patients (p=0.015), the concentration of serum immunoglobulin E, periostin, and TARC/CCL17, dose-dependently versus placebo (p<0.001). Patients with increased IL-13 activity (n=102), identified by baseline serum DPP-4 concentrations above median, showed an increased response to tralokinumab 300mg; more patients achieved IGA 0/1 (35% vs. 8%) and EASI75 (52% vs. 13%) than patients receiving placebo. The most frequent adverse events in all groups were nasopharyngitis (17%), upper respiratory tract infection (9%), headache (6%) and AD (6%).
Conclusion: Tralokinumab with TCS was more efficacious than TCS alone and demonstrated clinically relevant efficacy and an acceptable safety profile in patients with moderate-to-severe AD. DPP-4 might become a predictive marker for patients with AD who respond to tralokinumab 300mg, allowing a personalized medicinal approach.
Funding: This study was funded by MedImmune.
An investigator blinded randomized study evaluating hypochlorous acid (HOCl) in the treatment of atopic dermatitis-associated pruritus
Presenters: Berman B, Nestor M
Affiliation: Center for Clinical and Cosmetic Research and University of Miami Miller School of Medicine, Miami, FL
Background/Objective: Hypochlorous acid (HOCl) might potentially reduce pruritus in atopic dermatitis (AD) by its microbicidal qualities, particularly in reducing Staphylococcus aureus, and by its anti-inflammatory qualities that reduce the activities of histamine, leukotriene B4, and interleukin-2, all of which contribute to the pathophysiology of itch. Here, we present the results of a three-day study designed to evaluate the effect of HOCl on pruritus in patients with AD.
Methods: The study was conducted according to the protocol and in compliance with Good Clinical Practice (GCP) and other applicable regulatory requirements. This investigator-blinded, randomized Phase II, 72-hour study investigated the antipruritic effect of HOCl with patients diagnosed with AD. Subjects enrolled had AD as defined by the Hanifin criteria and had scored higher than 2 on an itch severity scale (0–4). Thirty subjects were enrolled, 20 randomized to the treatment group (HOCl), and 10 randomized to the untreated control group. Subjects used a HOCl containing solution BID or PRN for 72 hours and recorded applications in a diary. Subjects randomized to the untreated group received no treatment and were only instructed to come to follow-up visits for study-specific assessments.
The three primary measures used were Participant Global Assessment (PGA), Investigator Global Assessment (IGA), and Visual Analog Scale (VAS) itch score. Adverse events (AEs) and serious adverse events (SAEs) and incidence of local skin reactions leading to discontinuation were recorded as well. Measurements were taken at baseline, 24 hours, and 72 hours post-treatment. Photographs of representative areas of affected skin were taken.
Results: The mean VAS itch score between the two groups was similar at baseline. Mean change in PGA and IGA scores between baseline and 72 hours both significantly decreased in favor of the HOCl treatment group (PGA: p value=0.128; IGA: p=0.012). The mean itch VAS scores between the treated and untreated groups were significantly different between baseline and 72 hours post-application, with the percent mean change shown to be significantly lower (improved) in the HOCl treated group.
The analysis showed 73.7 percent of the subjects in the HOCl treated and 30.0 percent of the subjects in the untreated group experienced a reduction in itching between baseline and 72 hours after initial application. There were no treatment related discontinuations or SAEs.
Conclusion: This study demonstrated that application of HOCl-containing solution leads to a reduction in itching associated with AD at 24 hours with significantly better results when compared to the untreated cohort at 72 hours.
A real-world study evaluating adequacy of existing systemic treatments for patients with moderate-to-severe atopic dermatitis (AD-QUEST): baseline treatment patterns and unmet needs assessment
Presenters: Wei W1, Ghorayeb W2, Andria ML3, Walker V4, Chao J3, Schnitzer J2, Kennedy M3, Chen Z3; Belland A4, White J4, Silverberg JI5
Affiliations: 1Formerly of Sanofi, Bridgewater, NJ; 2Sanofi, Bridgewater, NJ; 3Regeneron Pharmaceuticals, Inc., Tarrytown, NY; 4Optum, Eden Prairie, MN; 5Northwestern University Feinberg School of Medicine, Chicago, IL
Objective: To evaluate potential unmet needs in the treatment of moderate-to-severe atopic dermatitis (AD) from a patient perspective.
Methods: Adults with an AD diagnosis in the last five years and a prescription for systemic treatment in the last six months were identified using claims data from Optum Research Database. Patients with self-assessed moderate-to-severe AD were invited to participate in monthly surveys over 12 months about disease signs and symptoms, quality of life (QoL) and AD treatment. We report baseline survey data.
Results: Of 6,000 patients invited to participate, 1,485 responded and 801 were eligible for inclusion (mean age: 45 years; female: 72%; Caucasian: 84%; employed: 79%; AD severity [Rajka & Langeland criteria]: moderate 74%, severe 26%). In the 12 months before baseline, 38 percent and 36 percent reported no remission or less than three months remission from AD. In the month before baseline, most reported using topical corticosteroids (64%) or calcineurin inhibitors (8%), some reported using antihistamines (38%), and a few reported using systemic steroids (11%) or immunosuppressants (5%). In the same period over 81 percent reported AD flares (1: 23%; 2: 20%; ?3: 38%), of which, 65 percent and 22 percent had partial or no recovery. Patients experiencing a flare versus those with no flare at baseline reported significantly worse POEM (13.5 vs. 6.2), peak pruritus NRS (worst itch in previous 24 hours: 6.3 vs. 3.5) and DLQI scores (8.6 vs. 3.7), and greater work productivity loss in previous seven days (8.2 vs. 3.4) (all P<0.001).
Conclusion: This suggests that despite standard-of-care treatments, adults with moderate-to-severe AD report disease symptoms, recurrent flares, and impaired QoL, suggesting unmet therapeutic needs.
Funding/Disclosures: Wenhui Wei is a former employee and current stockholder of Sanofi and an employee of Regeneron Pharmaceuticals, Inc. Eric Ghorayeb and James Schnitzer are employees of and stockholders in Sanofi. Michael Andria, Jingdong Chao, Martha Kennedy and Zhen Chen are employees of and stockholders in Regeneron Pharmaceuticals, Inc. Valery Walker, Angela Belland, and John White are employees of Optum, a company that received research funding for the current study. Jonathan Silverberg is a member of an institution that received research funding for the current study. This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Cemiplimab (REGN2810), a fully human anti-PD-1 monoclonal antibody, for patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Initial safety and efficacy from expansion cohorts of Phase I study
Presenters: Papadopoulos KP1,Owonikoko TK2, Johnson ML3, Bra?a I4, Gil-Martin M5, Perez RP6, Moreno V7, Salama AK8, Calvo E9,Yee NS10, Safran H11, González-Martín A12, Aljumaily R13, Mahadevan D14, Mohan KK15, Li J16, Stankevich E15, Israel Lowy I15, Fury MG15, Homsi J17
Affiliations: 1South Texas Accelerated Research Therapeutics, San Antonio, TX; 2Emory Winship Cancer Institute, Atlanta, GA; 3Sarah Cannon Research Institute, Nashville, TN; 4Vall D’HebronInstitute of Oncology, Barcelona, Spain; 5InstitutCatalàd’Oncologia, Barcelona, Spain; 6Unversity of Kansas, Fairway, KS; 7START Madrid Fundacion Jimenez Diaz, Madrid, Spain; 8Duke University Medical Center, Durham, NC; 9START Madrid, Hospital Madrid Norte Sanchinarro, Madrid, Spain; 10Penn State Cancer Institute, Hershey, PA; 11Miriam Hospital, Providence, RI; 12Formerly of MD Anderson International España, Madrid, Spain; 13University of Oklahoma Health Sciences Center, Oklahoma City, OK; 14Formerly of University of Arizona Cancer Center, Tucson, AZ; 15Regeneron Pharmaceuticals Inc., Tarrytown, NY; 16Regeneron Pharmaceuticals Inc., Basking Ridge, NJ; 17Formerly of Banner MD Anderson Cancer, Gilbert, AZ.
Background/Objective: Cemiplimab (REGN2810) is a human immunoglobulin G4 monoclonal antibody directed against PD-1.1. Phase I results from the first 60 patients with advanced solid tumors showed no dose-limiting toxicities. The most common treatment-related adverse events (AEs) in these patients were fatigue (28%), arthralgia (12%), and nausea(12%); the overall response rate was 18 percent. Cemiplimab 3mg/kg every two weeks (Q2W) was selected for further study in Expansion Cohorts. As of April 27, 2017, 392 patients have been enrolled in the Phase I study. The coprimary objectives of the CSCC Expansion Cohorts of this Phase I open-label study were to characterize the safety and tolerability of intravenous cemiplimab 3mg/kg and to evaluate the efficacy of cemiplimab by measuring overall response rate (ORR).
Methods: CSCC Expansion Cohorts (NCT02383212): Cohort 7 enrolled 10 patients with mCSCC, and Cohort 8 enrolled 16 patients with unresectable locally and/or regionally advanced CSCC. All patients received cemiplimab 3mg/kg Q2W for up to 48 weeks (if no progression or intolerance), followed by post-treatment follow-up. There was an option for re-treatment for patients who experienced disease progression during post-treatment follow-up, but no CSCC patients required this re-treatment option at the time of this study. All patients underwent tumor imaging every eight weeks, and response assessments were per RECIST 1.1. Research biopsies were performed at baseline and at Day 29. Subjects included scored a 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status, had a measurable disease by RECIST 1.1, had adequate organ function (bone marrow, kidney, liver), were in the mCSCC(M1): Expansion Cohort 7 and/or the unresectablelocally and/or regionally advanced CSCC (M0): Expansion Cohort 8. Exclusion criteria included presence of an autoimmune disease within five years, active brain metastases, or other invasive malignancy within five years (no exclusion for tumors considered cured by localized treatment), immunosuppressive doses of steroids (>10mg prednisone daily or equivalent), systemic antitumor treatment within four weeks of initial dose of cemiplimab, history of solid organ transplant, and tumors of lip or eyelid not eligible for CSCC cohorts.
Results: Investigator-assessed preliminary ORR (complete response [CR] + partial response [PR] + one unconfirmed PR) by RECIST 1.1 was 46.2 percent (12/26 patients; 95% confidence interval [CI]: 26.6–66.6; intent-to-treat [ITT] population). Disease control rate (DCR = ORR + stable disease [SD]) was 69.2 percent (18/26 patients; 95% CI: 48.2–85.7). Cemiplimab also produced rapid, deep, and durable tumor reductions in target lesions in both cohorts. As of April 27, 2017 (data cut-off date), 26 patients (median age, 73 years) from the CSCC expansions cohorts have been treated with cemiplimab. A total of 17 of 21 evaluated tumors (81%) were positive (?1%) for tumor expression of PD-L1 by immunohistochemistry. There was no apparent association between PD-L1 immunohistochemistry results and objective responses. The most common treatment-emergent adverse event (AEs) were fatigue, occurring among six patients. Two patients discontinued study treatment after treatment-related AEs: an 86-year-old woman developed a Grade 3 rash after three doses (she continued post-treatment follow-up) and an 88-year old male withdrew consent following Grade 3 transaminase elevation and Grade 2 fatigue after six doses. There were two deaths within 30 days of last dose of study drug, both considered unrelated to study drug.
Conclusion: This is the first prospective study of a PD-1 inhibitor in patients with advanced CSCC. Cemiplimab was generally well tolerated in CSCC in this predominantly older population. Both locally advanced and mCSCC are highly responsive to cemiplimab (combined ORR 46.2%), and durability is emerging. Eighty-one percent of pre-treatment tumor samples were PD-L1 positive. A unifying characteristic of cutaneous malignancies appears to be responsiveness to immune checkpoint inhibition. A Phase II study is ongoing in patients with unresectablelocally advanced and mCSCC(NCT02760498).
Funding/Disclosures: This study was funded by Regeneron Pharmaceuticals Inc, and Sanofi. Dr. Papadopoulos has received institutional research funding from Regeneron and Sanofi. Taofeek Owonikoko holds a consulting/advisory role for Regeneron. Melissa Johnson receives research funding from Regeneron. Raymond Perez receives institutional research funding from Regeneron. Emiliano Calvo receives institutional research funding from Sanofi. Nelson Yee receives institutional research funding from Regeneron. Kosalai Mohan, Jingjin Li, Elizabeth Stankevich, Israel Lowy, Matthew Fury, are stockholders and employees of Regeneron Pharmaceuticals, Inc. Matthew Fury also receives research funding, institutional patents, royalties, and other intellectual property from Regeneron. Jade Homsi receives research funding from Regeneron.
Safety and efficacy of A-101 hydrogen peroxide topical solution 40% in adults with seborrheic keratosis: results from the Phase III, randomized, double-blind, vehicle-controlled, parallel-group study
Presenters: Draelos ZD1, Kempers SE2, Smith SR3, Wilson DC4; Powala C5, Bradshaw M6; Estes E5; Shanler S5
Affiliations: 1Dermatology Consulting Services, High Point, NC; 2Minnesota Clinical Study Center, Fridley, MN; 3California Dermatology & Clinical Research Institute, Encinitas, CA; 4The Education and Research Foundation, Inc., Lynchburg, VA; 5Aclaris Therapeutics, Malvern, PA
Objective: Seborrheic keratosis (SK) is one of the most common benign skin lesions, affecting over 80 million Americans, yet there is no United States Food and Drug Administration (FDA)-approved treatment available. The purpose of this study was to evaluate the safety and efficacy of a proprietary 40% hydrogen peroxide topical solution (A-101) versus its matching vehicle for the treatment of seborrheic keratosis.
Design: Adults with four eligible SK lesions identified by the study investigator were randomized 1:1 to A-101 or a matching A-101 vehicle. Eligible lesions were stable, typical SKs, measuring 5 to 15mm in both width and length and less than 2mm in thickness. Subjects were required to present with at least one lesion on the trunk or extremities and at least one lesion on the face. All treatments were performed by a non- physician sub-investigator to maintain blinding. All lesions were treated on Day 1. Previously treated SK lesions with a Physician’s Lesion Assessment score over 0 were re-treated on Day 22 (PLA scale: 0=clear, 1=near clear, 2=thickness ?1mm, and 3=thickness>1mm). At Day 106, the investigator assessed the lesions using the validated PLA scale.
Results: Total of 450 subjects were enrolled. At Day 106, significantly more subjects receiving A-101 (intent-to-treat ITT population) completely cleared (PLA=0) all four lesions (4% vs. 0%, P<0 .002) and 3 of 4 lesions (13.5% vs. 0%, P<0.0001) versus vehicle in the primary and secondary endpoints, respectively. In the a priori exploratory analyses (per protocol population [PPP], n=439), significantly higher mean per-subject percentage of lesions achieving clear or near clear (PLA?1) was observed in the A-101 arm (47.5% vs. 10.2%; P<0.0001). Significantly higher mean per-subject percentage of facial lesions achieving clear or near clear (PLA?1) was also observed (64.4% vs.15.0% at Day 106; P<.0001). Adverse events were comparable between groups.
Local skin reactions were predominantly mild and generally resolved by Day 106. At all visits, atrophy, erosion, hypopigmentation, scarring, or ulceration were reported for at least four percent of lesions.
Conclusion: A-101, a 40% hydrogen peroxide topical solution, is a safe, effective, and well-tolerated treatment for SK. If approved, it would offer the first FDA-approved topical treatment for SK.
Long-term results of investigator-assessed efficacy and safety of 200mg dose of sonidegib for locally advanced basal cell carcinoma: 30-month BOLT analysis
Presenters: Migden M1, Lewis KD2
Affiliations: 1University of Texas MD Anderson Cancer Center, Departments of Dermatology, Division of Internal Medicine, and Head and Neck Surgery, Division of Surgery, Houston, TX; 2University of Colorado Denver, School of Medicine, Division of Medical Oncology, Denver, CO
Background/Objective: The 200mg dose of sonidegib was approved in 2015 in the European Union, Switzerland, Australia, and the United States for the treatment of patients with locally advanced basal cell carcinoma (laBCC) who are not amenable to curative surgery or radiation therapy. In both Switzerland and Australia, sonidegib is also approved for the treatment of metastatic BCC (mBCC). Sonidegib is a selective smoothened (SMO) inhibitor that blocks hedgehog pathway signaling. Approvals were based on results from the pivotal BOLT Phase II clinical trial (NCT01327053). Efficacy and safety data from BOLT were assessed by both investigator and central review. Here, we report the investigator-assessed efficacy and safety data of sonidegib 200mg QD from the 30-month analysis.
Methods: BOLT is a randomized, double-blind clinical trial that was conducted in 58 centers across 12 countries. Patients received either 200mg or 800mg of sonidegib once daily. Only the 200mg dose data will be presented here, as this dose was found in earlier studies to be more tolerable and equally as effective as the higher dose. As a primary endpoint, investigators evaluated objective response rate (ORR), which is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor evaluations were done using BCC-modified Response Evaluation Criteria In Solid Tumors (mRECIST) for laBCC. Sonidegib safety was monitored, including the monitoring of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Results: In patients with laBCC who received sonidegib 200mg (n=66), the investigator-assessed ORR was 71 percent. Median overall survival was not reached at this time point, but the two-year overall survival rate was 93 percent. Tumor responses were durable with a median duration of response of 15.7 months. At the 30-month data cutoff, the median duration of PFS was 19.4 months. One death was reported in the 200mg dose arm of patients with laBCC, but it was not considered to be related to study treatment. The safety profile of sonidegib 200mg was manageable, and no new safety concerns were found compared to the earlier BOLT data analyses. In summary, 43 percent of patients experienced grade 3/4 adverse events and AEs requiring dose interruptions/reductions. AEs that led to discontinuation occurred in 30 percent of patients, and the most commonly reported AEs included muscle spasms (56%), alopecia (52%), and dysgeusia (47%).
Conclusion: In the BOLT 30-month analysis, sonidegib 200mg QD provided sustained efficacy and a continued long-term acceptable safety profile in patients with laBCC. Interestingly, both the median DOR and median PFS data were higher when assessed by central review compared to investigator review. Given the stringent criteria used to assess tumor responses in the BOLT trial, these data support the use of sonidegib 200mg QD in patients with laBCC when used according to local treatment guidelines.
Perceptions regarding use of anti-tumor necrosis factor treatments for women of childbearing age among healthcare professionals
Presenters: Voorhees AV1, Afzali A2, Schwartzman S3, Ecoffet C4, Pisenti L5, Stark J5, Yassine M5, Abraham B6
Affiliations: 1Eastern Virginia Medical School, Norfolk, VA; 2The Ohio State University Wexner Medical Center, Columbus, OH; 3Hospital for Special Surgery, New York, NY; 4UCB Pharma, Brussels, Belgium; 5UCB Pharma, Smyrna, GA; 6Houston Methodist Hospital, Houston, TX
Background/Objective: For women with chronic inflammatory diseases (e.g., psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, inflammatory bowel disease), disease onset, diagnosis, and treatment initiation often overlap with peak reproductive years. High disease activity is associated with increased risk of pregnancy complications and adverse outcomes, and achieving disease control is therefore an important goal for the success of these pregnancies. Tumor necrosis factor antagonists (anti-TNFs) are effective treatments, but use among women of childbearing age (WoCBA) varies due to differing attitudes regarding their safety profiles versus benefits. This survey aimed to better understand perceptions and attitudes of healthcare professionals (HCPs) across different specialties regarding treatment of WoCBA patients with anti-TNFs during pregnancy and lactation.
Methods: An online survey was conducted in the United States on July 6, 2017, by SERMO RealTime. WoCBA was defined as women between the ages of 18 and 45 years. Survey participants included dermatologists (DM), gastroenterologists (GI), rheumatologists (RA) and obstetricians/gynecologists (OB).
Results: Two-hundred and fifty-six HCPs participated in the survey, including 53 DMs, 50 GIs, 50 RAs, 50 OBs. Half of the female patient population across specialties were WoCBA. DMs had the lowest proportion (27%) of female patients prescribed anti-TNFs (GI: 31%; RA: 43%). While physicians indicated being comfortable prescribing anti-TNFs for WoCBA patients, concerns were more prevalent once patients actively started family planning. DMs (57%) and OBs (62%) were more likely to recommend discontinuation of anti-TNFs before conception than GIs (36%) and RAs (46%); 45 percent of DMs and 54 percent of OBs agreed that WoCBA patients should stop anti-TNFs once they are pregnant (compared to <35% GIs and RAs). GIs (46%) and RAs (42%) agreed more strongly than DMs (15%) and OB (20%)on making disease control during pregnancy their priority . Only 17 percent of DMs felt that disease control reduces the risk of pregnancy complications and adverse outcomes, compared to GIs (52%), RAs (42%) and OBs (28%). More DMs and OBs than GIs and RAs believed patients who are breastfeeding should not take anti-TNFs, although a high degree of uncertainty was indicated. Overall, HCPs believed that more safety data during and after pregnancy are needed to feel more comfortable with prescribing anti-TNFs to WoCBA patients who are or might become pregnant in the future.
Conclusion: Our survey demonstrates the variability in clinical management of women with inflammatory or autoimmune diseases. Uncertainty about risks of anti-TNF use during pregnancy and lactation is common. Further research and multidisciplinary engagement among HCPs are needed to discuss and safely treat WoCBA.
Fundings/Disclosures: AVV: Consultant for: Dermira, Novartis, Celgene, AbbVie; board member: Dermira, Novartis, Celgene, AbbVie, Allergan, Derm Tech, Valeant, WebMD; ex-spouse pension: Merck; AA: Consultant for AbbVie, Takeda, UCB Pharma, research grant support from AbbVie, non-profit consultant and board member for IBD Horizons; SS: Consultant for Abbvie, Antares, Genentech, Janssen, Lilly, Novartis, Pfizer, Regeneron, Sanofi, UCB Pharma; speaker fees: Abbvie, Janssen, Genentech, Pfizer, UCB Pharma, Crescendo, Novartis; board member: Crescendo Biosciences, Discus Analytics, National Psoriasis Foundation; CE, LP, JS, MY: Employee of UCB Pharma; MC: Employee of Dermira Inc; BA: Grant/research support: Janssen, UCB Pharma; speaker’s fees: AbbVie, American Reagent, Janssen, UCB Pharma
Confirmatory psychometric evaluation of the axillary sweating daily diary: a validated patient-reported outcome measure to assess axillary hyperhidrosis sweating severity
Presenters: Glaser DA1,1 Hebert AA2, Fehnel S3, DiBenedetti D3, Nelson L3, Drew J4, Pariser DM5
Affiliations: 1Saint Louis University, St. Louis, MO; 2UTHealth McGovern Medical School at Houston, Houston, TX; 3RTI Health Solutions, Research Triangle Park, NC; 4Dermira, Inc., Menlo Park, CA; 5Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VA
Background/Objective: Hyperhidrosis affects an estimated 4.8 percent of the United States population; approximately three-quarters of patients experience negative psychological effects, with anxiety and depression occurring over
3.5?times more frequently in people with hyperhidrosis than in people without it. Despite high prevalence and burden of disease, few disease-specific outcome measures are available. The Hyperhidrosis Disease Severity Scale (HDSS) is widely used in clinical studies and well understood in clinical practice; however, it does not conform to current regulatory standards for patient-reported outcome (PRO) measures used to support product approvals and labeling. The four-item Axillary Sweating Daily Diary (ASDD) and a child-specific two?item version (ASDD-C) for use in patients between 9 and 16 years of age were developed according to current regulatory standards. The ASDD/ASDD-C axillary sweating severity item (Item 2) was specifically developed for use as an endpoint in clinical trials in support of approval and labeling (and also as a useful clinical parameter). In addition to the ASDD, patients 16 years of age or younger were asked to complete six Weekly Impact Items designed to assess the impact and bother of hyperhidrosis on daily activities and a single?item Patient Global Impression of Change (PGIC) to assess overall change in sweating severity. Initial psychometric evaluation of the ASDD was conducted using data from a Phase II study of topical glycopyrronium tosylate (GT; formerly DRM04), an investigational treatment for primary axillary hyperhidrosis in patients nine years of age or older; results have been previously reported and provide preliminary support for the use of this measure to evaluate the efficacy of axillary hyperhidrosis treatment in clinical trials. In this study, we aimed to confirm and extend the psychometric evidence supporting ASDD/ASDD-C axillary sweating severity item (Item 2) based on pooled data from two Phase III clinical trials of GT: ATMOS-1
(DRM04-HH04; NCT02530281) and ATMOS-2 (DRM04-HH05; NCT02530294)
Methods: ATMOS-1 and ATMOS-2 were Phase III, multicenter (ATMOS-1: sites in the United States and Germany; ATMOS-2: sites in United States), parallel-group, four-week, double-blind clinical trials in which patients with primary axillary hyperhidrosis were randomized (2:1) to GT or vehicle. Eligible patients were at least nine years of age (patients <16 years were only recruited at United States sites) and had primary axillary hyperhidrosis for at least six months, with gravimetrically measured sweat production of at least 50mg per five minutes in each axilla, ASDD/ASDD-C axillary sweating severity item (Item 2) score 4 or above, and Hyperhidrosis Disease Severity Scale (HDSS) Grade 3 or 4. ASDD/ASDD-C Item 2 responses and sweat production were assessed in two age groups (?9 years and ?16 years). ASDD/ASDD-C items were scored as a weekly average of daily responses; at least four days of daily data were required for analysis. Weekly Impact Items and PGIC were included to evaluate construct validity. Potential floor and ceiling effects and nonresponse bias were evaluated based on both summary statistics and graphical techniques. Test-retest reliability was evaluated through the computation of intraclass correlation coefficients (ICCs) between Week 3 and Week 4; a value of at least 0.70 was considered acceptable. Construct validity was evaluated at Week 4 based on correlations between ASDD/ASDD-C Item 2 and ASDD items related to the impact and bother of sweating (Items 3 and 4, respectively), HDSS, sweat production, and other PRO measures, as available. All statistical tests were two-tailed using a type I error rate of one percent (?=0.01).
Results. The pooled Phase III study population (n=697) included 665 patients who were at least 16 years of age and 32 patients aged 9 to 15 years of age. The response distribution for the ASDD/ASDD-C axillary sweating severity item (Item 2) demonstrated no floor or ceiling effect and no nonresponse bias. Construct validity was supported by strong correlations between ASDD Item 2 and the ASDD items addressing the impact and bother of axillary sweating (Items 3 and 4, respectively).
Test-retest reliability was supported by ICCs of 0.93 for both age subgroups, which is well above the 0.70 criterion and within the confidence interval (CI) of the Phase II estimate of 0.91 (95% CI: 0.87, 0.94. The ASDD/ASDD-C Item 2 responsiveness, or ability to detect change in sweating severity, was demonstrated by large effect sizes and correlations that were within the expected range for the change in ASDD/ASDD-C Item 2 and the change in the gravimetric measures of sweat production.
Conclusion: The current study confirms and extends the psychometric evidence supporting the
ASDD/ASDD?C as a new PRO measure developed according to current regulatory standards. The psychometric findings presented here continue to support use of the ASDD/ASDD-C axillary sweating severity item (Item 2) as an endpoint in assessing the efficacy of treatments for patients with axillary hyperhidrosis.
Funding/Disclosures: This study was funded by Dermira, Inc. 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. Dana DiBenedetti, Lauren Nelson, and Sheri Fehnel are employees of RTI Health Solutions. Janice Drew is an employee of Dermira, Inc. David M. Pariser is a consultant and investigator for Dermira, Inc.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled, Phase IIIb clinical trial in patients with moderate-to-severe genital psoriasis
Presenters: Ryan C1, Menter A2, Guenther L3, Blauvelt A4, Bissonnette R5, Yang FE6, Potts Bleakman A6; Amato DA6
Affiliations: 1Department of Dermatology, St. Vincent’s University Hospital, Dublin, Ireland; 2Menter Cosmetic Institute, Dallas, TX; 3Guenther Dermatology Research Centre, Ontario, Canada; 4Oregon Medical research Center, Portland, OR; 5Innovaderm Research, Quebec, Canada; 6Eli Lilly and Company, Indianapolis, IN
Background/Objectives: Genital psoriasis (gen-pso) is common among patients with plaque psoriasis. The condition negatively impacts quality of life and sexual health. Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for the treatment of plaque psoriasis. This study’s objective was to evaluate the effect of IXE on gen-pso compared to placebo (PBO) during 12 weeks of treatment.
Methods: Patients with moderate-to-severe gen-pso (n=149) were randomized in a 1:1 ratio to receive either PBO (n=74) or 80mg IXE every two weeks (Q2W) following a starting dose of 160mg IXE (n=75). The primary endpoint was the percentage of patients achieving a 0 or 1 score on the 6-point static Physician’s Global Assessment of Genitalia (sPGA-G [0,1]) at Week 12. Major secondary endpoints included the percentage of patients achieving a 0 or 1 score on the 6-point overall sPGA (sPGA [0,1]), at least a three-point improvement on the 11-point Genital Itch (gen-itch) Numeric Rating Scale (NRS) for patients with a baseline score of at least 3, and a 0 or 1 score for the 5-point Sexual Frequency Questionnaire Item 2 (SFQ-item 2 [0,1]) (indicating that the frequency of sexual activity is never or rarely limited by gen-pso) for patients with a baseline SFQ-Item 2 score of at least 2. Treatment comparisons were made using logistic regression analysis with non-responder imputation for missing data. Clinicaltrials.gov ID: NCT02718898.
Results: IXE Q2W treatment led to significantly greater sPGA-G (0, 1) response rates (73.3%) than PBO (8.1%) at Week 12 (p<0.001). Similarly, overall sPGA (0, 1) response rates were significantly greater with IXE Q2W (73.3%) compared to PBO (2.7%, p<0.001). IXE Q2W led to significantly greater gen-itch NRS response rate (59.7%) at Week 12 versus PBO (8.3%, p<0.001). Significantly more patients achieved SFQ-item 2 (0, 1) with IXE Q2W (78.4%) than PBO (21.4%, p<0.001). Significant improvements in response rates were observed by Week 1 for sPGA-G (0,1) (p<0.01), overall sPGA (0,1) (p<0.001), and SFQ-item 2 (0, 1) (p<0.05), and by Week 2 for gen-itch NRS (p<0.001). Frequencies of treatment-emergent adverse events (TEAEs) through Week 12 were 56.0 percent and 44.6 percent in IXE Q2W and PBO groups, respectively; the majority were mild or moderate in severity. Common TEAEs in the IXE Q2W population included upper respiratory tract infections, injection site reactions, headache, oropharyngeal pain, and pruritus. No cases of candidiasis were reported, no deaths occurred, and only one (1.4%) serious adverse event was reported in a patient receiving PBO.
Conclusion: IXE Q2W was superior to PBO for the primary and all major secondary endpoints as early as Week 1 and safety outcomes were comparable to previously reported IXE Phase III trials. These results indicate that IXE is an efficacious treatment of moderate-to-severe gen-pso and minimizes how often gen-pso limits the frequency of sexual activity.
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.
Clinical efficacy of tildrakizumab, an anti–IL-23p19 monoclonal antibody, in patients with chronic plaque psoriasis over two years of treatment: Results from long-term extensions to two Phase III clinical studies (reSURFACE 1 and reSURFACE 2)
Presenters: Papp K1, Reich K2, Blauvelt A3, Thaçi D4, Sinclair R5, Tyring SK6, Cichanowitz N7, Green S7, Li Q,7 La Rosa C7
Affiliations: 1Probity Medical Research, Waterloo, ON, Canada; 2SCIderm Research Institute and Dermatologikum Hamburg, Hamburg, Germany; 3Oregon Medical Research Center, Portland, Oregon; 4Comprehensive Center for Inflammation Medicine, University Medical School Schleswig-Holstein, University of Lübeck, Lübeck, Germany; 5University of Melbourne, Melbourne, VIC, Australia; 6Department of Dermatology, University of Texas, Houston, Texas; 7Merck & Co., Inc., Kenilworth, New Jersey
Background/Objective: Tildrakizumab is a high-affinity, humanized, anti-IL-23p19 monoclonal antibody that has demonstrated efficacy in the treatment of chronic plaque psoriasis in two Phase III studies (reSURFACE 1 and 2). Extensions of these studies are ongoing. In this analysis, we present preliminary data evaluating maintenance of response in patients who were responders to tildrakizumab upon entering the extension periods and who maintained response a year into the extensions (a total of at least 2 years of treatment).
Methods: The reSURFACE base studies are three-part, double-blinded, randomized, placebo-controlled studies in adult patients with moderate-to-severe chronic plaque psoriasis (body surface area involvement ?10%, Physician’s Global Assessment [PGA] score ?3, and Psoriasis Area and Severity Index [PASI] ?12). Tildrakizumab 200mg and 100mg were evaluated for 64 weeks (reSURFACE 1; NCT01722331) and 52 weeks (reSURFACE 2; NCT01729754), respectively. Patients were eligible for the optional long-term extensions if they completed the base studies and achieved PASI ?50 at the end of the base studies (for reSURFACE 1 only, patients had to have received an active dose of tildrakizumab within 12 weeks of the end of the base study). Patients received the same dose of tildrakizumab (200mg or 100mg every 12 weeks) as they received at the completion of the base studies. Administration was open label after database lock for the base studies. The full analysis set (patients with at least 1 dose of extension treatment based on assigned treatment) was the primary efficacy population. The efficacy objective during the extension period was evaluation of maintenance of efficacy endpoints (i.e., proportion of PASI 50, 75, 90, and 100 responders 1 year into the extension among PASI 50, 75, 90, and 100 responders at the start of the extension) prespecified to be based on observed data. No statistical analyses were planned for comparison between doses.
Results: In reSURFACE 1, 772 patients entered, 638 completed the base study, and 506 entered the extension; in reSURFACE 2, 1,090 patients entered, 756 patients completed the base study, and 731 entered the extension. In reSURFACE 1, in patients entering the extension on tildrakizumab 200mg, PASI 50/75/90/100 was maintained by 97%/91%/82%/63% (out of 255/208/135/70 patients with data at 1 year); in patients on tildrakizumab 100mg, PASI 50/75/90/100 was maintained by 98%/90%/74%/53% (out of 219/195/121/70 patients with data at 1 year). In patients entering the extension on tildrakizumab 200 mg in reSURFACE 2, PASI 50/75/90/100 was maintained by and 97%/88%/84%/70% (out of 330/293/191/97 patients with data at 1 year); for those on tildrakizumab 100mg, PASI 50/75/90/100 was maintained by 99%/92%/84%/66% (out of 352/327/249/125 patients with data at 1 year).
Conclusion: Tildrakizumab 100mg and 200mg demonstrated maintenance of efficacy in the treatment of moderate-to-severe chronic plaque psoriasis for at least two years of treatment.
Funding: Study sponsored by Merck & Co. Analyses previously presented at the 26th European Academy of Dermatology and Venereology Congress, Geneva, Switzerland, 2017.
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.
Long-term efficacy of brodalumab for the treatment of moderate-to-severe psoriasis: data from a pivotal Phase III clinical trial
Presenters: Menter A1, Sobell J2, Silverberg JI3, Lebwohl M4, Rastogi S5, Pillai R6, Israel RJ5
Affiliations: 1Baylor University Medical Center, Dallas, TX; 2SkinCare Physicians, Chestnut Hill, MA; 3Northwestern University Feinberg School of Medicine, Chicago, IL; 4Icahn School of Medicine at Mount Sinai, New York, NY; 5Valeant Pharmaceuticals North America LLC, Bridgewater, NJ; 6Dow Pharmaceutical Sciences, Petaluma, CA
Background/Objective: Brodalumab is a fully human anti-interleukin-17 receptor A (IL-17RA) monoclonal antibody that antagonizes the action of specific inflammatory cytokines involved in psoriasis. Pivotal Phase III clinical trials demonstrated the efficacy and safety of brodalumab through 52 weeks of treatment in patients with moderate-to-severe psoriasis. We evaluated the efficacy of brodalumab in psoriasis from Week 52 through Week 120. Data were derived from the long-term, open-label extension study of a 52-week, randomized, double-blind, placebo- and active comparator-controlled clinical trial (AMAGINE-2).
Methods: Patients received brodalumab 210mg or 140mg every two weeks (Q2W), ustekinumab, or placebo during a 12-week induction phase, followed by a maintenance phase through Week 52. During the maintenance phase, patients receiving brodalumab were rerandomized to a different dose and interval of brodalumab (210mg or 140mg Q2W, Q4W, or Q8W), patients receiving placebo were switched to brodalumab 210mg Q2W, and patients receiving ustekinumab continued on ustekinumab. At Week 52, patients who received brodalumab during the maintenance phase continued receiving their maintenance dose of brodalumab, and patients who were taking ustekinumab switched to brodalumab 210mg Q2W. Data are presented for patients who received brodalumab 210mg Q2W (the FDA-approved dose) through Week 120 of the long-term extension phase.
Results: A total of 1,392 patients received brodalumab 210mg Q2W in the long-term extension phase. At Week 52, rates (95% confidence interval [CI]) of these patients for Psoriasis Area and Severity Index (PASI) 75-percent improvement (PASI 75), PASI 90, and PASI 100 were 90.6 percent (88.9%-92.2%), 77.6 percent (75.2%-79.9%), and 53.3 percent (50.5%-56.0%), respectively. Similarly, at Week 120, corresponding responder rates (95% CI) were 88.4 percent (86.0%-90.6%), 76.8 percent (73.6%-79.7%), and 56.2 percent (52.7%-59.7%), respectively. Success rates (95% CI), based on static physician’s global assessment score of 0 or 1, were 79.2 percent (76.8%-81.4%) and 76.6 percent (73.5%-79.6%) at Weeks 52 and 120, respectively. The patients who received continuous brodalumab 210mg Q2W (n=334) achieved Static Physician’s Global Assessment Score of 0 or 1, PASI 75, PASI 90, and PASI 100 response of 79.2, 86.5, 76.4, and 59.0 percent, respectively, through Week 120.
Conclusion: Treatment with brodalumab resulted in substantial psoriatic lesion clearing for more than two years in most patients with moderate-to-severe psoriasis.
Funding: This study was sponsored by Amgen Inc.
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.
Secukinumab is superior to ustekinumab in clearing skin of patients with moderate-to-severe plaque psoriasis: CLARITY, a randomized, controlled, Phase IIIb trial
Presenters: Bagel J1, Nia J2, Hashim P2, Patekar M3, de Vera A3, Hugot S3, Sheng K4, Xia S5, Muscianisi E4, Blauvelt A6, Lebwohl M2
Affiliations: 1Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ; 5Novartis Beijing Novartis Pharma Co. Ltd, Shanghai, China; 6Oregon Medical Research Center, Portland, OR
Background/Objective: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has previously demonstrated superior efficacy to ustekinumab in the Phase IIIb CLEAR study of moderate-to-severe plaque psoriasis. Here, we report 16-week results from CLARITY, the second head-to-head trial comparing secukinumab with ustekinumab.
Methods: In this ongoing multicenter, head-to-head, double-blind, parallel-group, Phase IIIb study (NCT02826603), patients were randomized 1:1 to receive subcutaneous secukinumab 300mg or ustekinumab per label. The co-primary objectives were to demonstrate the superiority of secukinumab over ustekinumab at Week 12 in relation to the proportion of patients with 1) 90-percent or more improvement from baseline Psoriasis Area and Severity Index (PASI 90) and 2) a score of 0/1 (clear/almost clear) on the Investigator’s Global Assessment (IGA mod 2011 0/1). Key secondary objectives included demonstrating the superiority of secukinumab over ustekinumab with respect to PASI 75 at Week 4; PASI 75 and 100 at Week 12; PASI 75, 90, 100; and IGA mod 2011 0/1 at Week 16. Missing values were handled by multiple imputation.
Results: At Week 12, both co-primary objectives were met, secukinumab 300 mg (n=550) was significantly superior to ustekinumab (n=552) for the proportion of patients achieving both PASI 90 (66.5% vs. 47.9%; P<0.0001) and IGA mod 2011 0/1 (72.3% vs 55.4%; P<0.0001) response rates. Additionally, all key secondary objectives were met. At Week 4, PASI 75 response rates were significantly superior with secukinumab 300mg compared to ustekinumab (40.2% vs 16.3%; P<0.0001). At Week 16, secukinumab 300mg demonstrated significantly superior response rates compared to ustekinumab for PASI 75 (91.7% vs. 79.8%; P<0.0001), PASI 90 (76.6% vs. 54.2%; P<0.0001), PASI 100 (45.3% vs. 26.7%; P<0.0001), and IGA mod 2011 0/1 (78.6% vs. 59.1%; P<0.0001). Furthermore, at Week 12, patients receiving secukinumab 300mg compared to ustekinumab had significantly greater PASI 75 (88.0% vs. 74.2%; P<0.0001) and PASI 100 (38.1% vs. 20.1%; P<0.0001) responses. Safety findings were consistent with the known safety profile of secukinumab.
Conclusion: Secukinumab demonstrated superior results with greater improvements compared to ustekinumab across all study outcomes at Weeks 4, 12, and 16 in patients with moderate-to-severe plaque psoriasis.
Funding: This research was sponsored by Novartis Pharma AG, Basel, Switzerland.
Secukinumab for the treatment of scalp, nail, and palmoplantar psoriasis
Presenters: Hawkes JE1,2, Lebwohl M2, Elewski B3, Kircik L2,4, Reich K5, Muscianisi E6, Gottlieb A7
Affiliations: 1The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3University of Alabama, Birmingham, AL; 4Indiana University School of Medicine, Indianapolis, IN; 5Dermatologikum Hamburg, Hamburg, Germany; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ 7New York Medical College, Valhalla, NY
Background/Objective: Psoriasis is a chronic, immune-mediated, systemic condition that commonly affects the scalp, nails, palms, and soles. Although psoriasis in these areas accounts for a small percentage of total body surface area, it often results in significant dysfunction and quality of life impairment. For instance, the highly visible nature of scalp psoriasis can cause embarrassment and discomfort. Psoriatic nail disease is often overlooked, causing cosmetic concerns and difficulty with tasks requiring manual dexterity. Palmoplantar psoriasis causes significant functional impairment compared with other psoriasis subtypes and can be recalcitrant to traditional systemic therapies. Until recently, there has been limited clinical research focused on less common and hard-to-treat subtypes or clinical features of psoriatic disease. Secukinumab, a human monoclonal antibody that selectively binds to and neutralizes interleukin-17A, has demonstrated efficacy for chronic plaque psoriasis in a structured Phase III development plan. Here we present a review of the efficacy and safety of secukinumab in patients with psoriasis affecting the scalp, nails, palms, and soles of the feet.
Methods: In three separate clinical trials designed specifically for each of these hard-to-treat areas, inclusion criteria included patients with moderate-to-severe scalp psoriasis (Psoriasis Scalp Severity Index [PSSI] ?12), patients with moderate-to-severe psoriasis with significant nail involvement (Nail Psoriasis Severity Index [NAPSI] ?16 with ?4 fingernails involved), and patients with moderate-to-severe palmoplantar psoriasis (palmoplantar Investigator’s Global Assessment [ppIGA] ?3), respectively. In all trials, patients received secukinumab 300mg or 150mg at baseline, Weeks 1, 2 and 3, and then every four weeks beginning at Week 4.
Results: The primary endpoint of each trial was met. In 102 patients with scalp psoriasis, PSSI 90-percent improvement response rates were significantly greater with secukinumab 300mg versus placebo at Week 12 (52.9% vs. 2.0%; P<0.001). One in 198 patients with nail psoriasis, mean NAPSI percent change from baseline to Week 16 was significantly greater in secukinumab 300mg (-45.3%) and secukinumab 150mg (-37.9%) groups compared to placebo (-10.8%; both P<0.0001). In 205 patients with nonpustular palmoplantar psoriasis, ppIGA0/1 was achieved at Week 16 by significantly more patients with secukinumab 300mg (33.3%) and secukinumab 150mg (22.1%) than with placebo (1.5%; both P<0.001). The safety of secukinumab in these trials was consistent with the safety profile observed in previous clinical trials, and no new safety signals were identified.
Conclusion: Secukinumab is a safe and effective treatment option in chronic plaque psoriasis and these hard-to-treat psoriasis subtypes as demonstrated in specifically designed prospective clinical trials.
Funding: This research was sponsored by Novartis Pharma AG, Basel, Switzerland, and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Radiographic progression of structural joint damage in patients with active psoriatic arthritis treated with ixekizumab over 52 weeks
Presenters: van der Heijde D1, Okada M2, Lee C3, Shuler CL3, Rathmann S3, Amato D3, Lin CY3, and Mease P4
Affiliations: 1Leiden University Medical Centre, Leiden, the Netherlands; 2St. Luke’s International Hospital, Tokyo, Japan; 3Eli Lilly and Company, Indianapolis, IN; 4Swedish Medical Center and University of Washington, Seattle, WA
Background/Objective: Ixekizumab (IXE), an anti-interleukin-17A monoclonal antibody, was shown to be superior to placebo (PBO) in clinical responses and in inhibition of the progression of structural joint damage in patients with psoriatic arthritis (PsA) treated for 24 weeks. Here, we assessed progression of structural joint damage in PsA patients with IXE for up to 52 weeks.
Methods: Biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with active PsA (n=417) entered into SPIRIT-P1 (NCT01695239), a double-blind Phase III trial. Patients must have had at least one joint erosion on the hand and foot confirmed by central x-ray reading or have had a C-reactive protein level less than 6mg/L at screening. A total of 417 patients were randomized to IXE 80mg every two (Q2W; n=103) or four weeks (Q4W; n=107) following a 160mg initial dose, PBO (n=106), or adalimumab 40mg every two weeks (ADA; active reference arm; n=101) for 24 weeks. In the Extension Period (EXT; Weeks 24–52), patients on PBO and ADA were re-randomized (1:1) to IXEQ2W or IXEQ4W at Week 16 (inadequate responders) or Week 24; patients on ADA underwent a washout prior to IXE treatment. All patients were assessed for structural joint damage using the van der Heijde modified PsA Total Sharp Score (mTSS, 0–528 scale). Two readers blinded to timepoint scored X-rays at Weeks 0, 24, and 52 independently and clinical data (average of readers). The mTSS was excluded from the prespecified analysis if the radiograph was taken after the scheduled visit date. In a post-hoc analysis, mTSS from a radiograph taken after the scheduled visit date was interpolated and considered as observed data. Any missing data at Week 52, in either presentation, were imputed using a linear extrapolation if they had at least one post-baseline value.
Results: Of the patients who had active PsA at Week 0, 381 patients (91.3%) entered the EXT, with 374 (98.2%) having radiographs collected during the EXT. Week 52 mean (SD) mTSS change from baseline were 0.54 (2.11) and 0.09 (1.0) for patients randomized to IXEQ4W and IXEQ2W at baseline, respectively. Similarly, post-hoc analysis changes at Week 52 were 0.47 (1.9) and 0.09 (0.9) for the IXEQ4W and IXEQ2W groups, respectively. The majority of patients on IXEQ2W or IXEQ4W exhibited no structural progression through one year of IXE treatment. In patients who switched from PBO or ADA to IXE, the Week 52 mean change from baseline mTSS values scores ranged from -0.03 to 0.41.
Conclusion: Over a 52-week period, minimal changes in mTSS were observed in patients with PsA entering the EXT and treated with IXEQ2W or IXEQ4W.
Secukinumab achievement of psoriatic arthritis disease activity score- (PASDAS) related remission: two-year results from a Phase III study
Presenters: Coates LC1, Gladman DD2, Nash P3, Fitzgerald O4, Kavanaugh A5, Rasouliyan L6, Pricop L7, Ding K7, Gaillez C8 (on behalf of the FUTURE 2 Study Group)
Affiliations: 1Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; 2Toronto Western Hospital, Toronto, ON, Canada; 3University of Queensland, Brisbane, Australia; 4St. Vincent’s University Hospital, Dublin, Ireland; 5UC San Diego School of Medicine, La Jolla, CA; 6RTI Health Solutions, Barcelona, Spain; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ; 8Novartis Pharma AG, Basel, Switzerland.
Background/Objective: Psoriatic Arthritis Disease Activity Score (PASDAS) assessing multiple facets of psoriatic arthritis (PsA) has been shown to distinguish treatment effect and perform better in statistical terms than traditional joint-only indices and could be used as a treatment target in clinical trials in PsA. Secukinumab significantly improved the signs and symptoms of PsA over 104 weeks in the FUTURE 2 study. This post-hoc analysis assessed the ability of secukinumab to achieve low disease activity (LDA) or remission (REM) using PASDAS through 104 weeks in the FUTURE 2 study.
Methods: The FUTURE 2 study design was previously published. PASDAS index is derived from Physician’s Global Visual Analog Scale, patient’s global VAS, SF-36 PCS, tender and swollen joint counts, Leeds enthesitis count, dactylitis count and c-reactive protein level with validated cut-points for high disease activity (HDA ?5.4), moderate disease activity (3.2< MoDA <5.4), 1.9<LDA ?3.2 and REM ?1.9.3
Results: PASDAS scores at baseline was similar across the three treatment groups. In the overall population at Week 16, PASDAS REM, LDA, and MoDA were achieved in 15.6 percent, 22.9 percent, and 49.0 percent, respectively, of patients treated with secukinumab 300 mg; of patients treated with secukinumab 150mg, 15.2 percent, 19.2 percent, and 42.4 percent, respectively; and of patients given placebo, 2.3 percent, 13.8 percent, and 44.8 percent, respectively. At Week 104, REM was achieved in 22.9 percent and 14.3 percent of patients treated with secukinumab 300mg and 150mg, respectively. In anti–TNF-naïve patients at Week 16, PASDAS REM, LDA, and MoDA were achieved in 18.5 percent, 27.7 percent, and 46.2 percent, respectively, of patients treated with secukinumab 300mg; of patients treated with secukinumab 150mg, 22.2 percent, 20.6 percent, and 42.9 percent, respectively; and of patients given placebo, 3.5 percent, 14.0 percent, and 45.6 percent, respectively. At Week 104 in anti–TNF-naïve patients, REM was achieved in 29.1 percent and 17.0 percent of patients treated with secukinumab 300mg and 150mg, respectively. In anti–TNF-inadequate response (IR) patients at Week 16, PASDAS REM, LDA, and MoDA were achieved in 9.7 percent, 12.9 percent, and 54.8 percent, respectively, of patients treated with secukinumab 300mg; of patients treated with secukinumab 150mg, 2.8 percent, 16.7 percent, and 41.7 percent, respectively; of patients given placebo, 0 percent, 13.3 percent, and 43.3 percent, respectively. At Week 104 in anti–TNF-IR patients, REM was achieved in 10.7 percent and 8.3 percent of patients treated with secukinumab 300mg and 150mg, respectively. The proportion of patients achieving PASDAS REM/LDA at Weeks 16 and 104 was similar, irrespective of time since first diagnosis, for both secukinumab doses. Secukinumab treated patients achieving PASDAS REM had significantly greater improvements in function, physical- and mental-health quality of life, and fatigue compared to HDA through Week 104.
Conclusion: At Week 16, PASDAS REM and LDA were achieved in 38.5 percent and 34.4 percent of patients treated with secukinumab 300mg and 150mg, respectively, versus 16.1 percent in the placebo group, with approximately 50 percent of patients achieving PASDAS REM and LDA in both secukinumab groups at Week 104. A higher proportion of anti–TNF-naïve patients treated with secukinumab achieved PASDAS REM or LDA than those treated with anti–TNF-IR through Week 104. Secukinumab treated patients achieving PASDAS REM had significantly greater improvements in function, quality of life, and fatigue.
Funding: This research was sponsored by Novartis Pharma AG in Basel, Switzerland.
Concurrent administration of ivermectin 1% cream with brimonidine 0.33% gel improves efficacy and tolerability in treatment of moderate-to-severe rosacea
Presenters: Gold LS1, Papp K2, Lynde C3, Lain E4, Gooderham M5, Johnson S6, Kerrouche N7, Schäfer G8
Affiliations: 1Department of Dermatology, Henry Ford Medical Center, Detroit, MI; 2K. Papp Clinical Research, Probity Medical Research, Waterloo, ON, Canada; 3Lynde Institute for Dermatology, Markham, ON, Canada; 4Austin Institute for Clinical Research, Pflugerville, TX; 5SKiN Centre for Dermatology, Probity Medical Research and Queen’s University Peterborough, ON, Canada; 6Johnson Dermatology, Fort Smith, AR; 7Galderma R&D, Sophia Antipolis, Biot, France, 8Galderma International, Paris, France
Background/Objective: Multiple studies have demonstrated the efficacy of ivermectin 1% (IVM) cream (inflammatory lesions) and brimonidine 0.33% (BR) gel (persistent erythema). This prospective study evaluated the efficacy and safety of IVM and BR versus their vehicles in moderate-to-severe rosacea.
Methods: This was a multicenter, randomized, double-blind, vehicle-controlled study in moderate-to-severe rosacea (Investigator Global Assessment [IGA] ?3). The study comprised three arms. The two active treatment arms were: 1) once-daily BR (morning) and IVM (evening) for 12 weeks (IVM+BR/12W; n=49); or 2) Once-daily BR vehicle for four weeks, followed by once-daily BR for eight weeks (morning), and once-daily IVM for 12 weeks (evening; IVM+BR/8W; n=46). The the vehicle arm stipulated once-daily BR vehicle (morning) and IVM vehicle (evening), 12 weeks (n=95). A general skin care regimen (cleanser/moisturizer/sunscreen) was provided/recommended. IGA (0–4), Clinician’s Erythema Assessment (CEA; 0–4), percent change from baseline inflammatory lesion count (ILC), percentage of subjects with 10- percent IL reduction, subject global rosacea improvement, and facial appearance questionnaire. Adverse events (AEs) were monitored throughout the study.
Results: The total IVM and BR population showed superior efficacy (Week 12, Hour 3; IGA success [clear/almost clear]) versus vehicle (55.8% vs. 36.8%, p=0.007); IVM and BR/12W showed better efficacy versus vehicle (61.2% vs. 36.8%, p=0.003) than IVM and BR/8W (50% vs. 36.8%, p=0.135). At Week 12, success increased for IVM and BR/12W (32.7%, Hour 0 [pre-BR application]; 61.2%, Hour 3 [post-BR application) and IVM and BR/8W (28.3%, Hour 0; 50%, Hour 3). CEA and median percent change in ILC improved with IVM and BR/12W and IVM and BR/8W vs vehicle (p<0.01). IVM and BR/12W trended toward higher efficacy. Eight treatment-related AEs in six subjects (3.2%) were reported (including treatment-related worsening of rosacea: 1 with IVM and BR, 3 with vehicle).
Conclusion: Administration of IVM cream with BR gel demonstrated good efficacy and safety. Early introduction of BR (Day 1; with a complete daily skin care regimen) might benefit efficacy and accelerate treatment success without impairing tolerability.
Funding: This analysis was funded by Galderma R&D. G. Schäfer and N. Kerrouche are employees of Galderma.
Cutaneous tolerability of a novel topical minocycline gel for the treatment of rosacea
Presenters: Bhatia N1, Ahmadyar M1, Hansra H2, Del Rosso J3, Baldwin H4, Daniels AM5
Affiliations: 1Therapeutics Clinical Research, San Diego, CA; 2BioPharmX, Inc., Menlo Park, CA; 3JDR Dermatology Research, LLC, Las Vegas, NV; 4The Acne Treatment and Research Center, Morristown, NJ
Background/Objective: Rosacea is a chronic and relapsing skin disorder that primarily involves the central face. Affecting at least 16 million people in the United States alone, rosacea can develop via genetic, immunologic, inflammatory, vascular, or environmental pathways. The papulopustular subtype resembles acne vulgaris in its formation of inflammatory papules, pustules, and plaques.
Minocycline is effective as a first-line systemic therapy for rosacea. It is thought that, like other tetracyclines, its anti-inflammatory properties are responsible. Unfortunately, oral and/or long-term use, as required in a chronic condition such as rosacea, might contribute to antibiotic resistance. Additionally, significant side effects such as gastrointestinal distress and vertigo might make oral minocycline intolerable. Therefore, another form of delivery is needed.
Methods: This was a Phase II feasibility study of 1% and 2% formulations of a novel topical minocycline gel. Nineteen adults with moderate-to-severe papulopustular rosacea participated. Skin diseases, prohibited comorbidities and treatments, and pregnancy were exclusionary.
Treatment was open-label and nonrandomized. Subjects applied the assigned gel to the face once per day for 12 weeks. Numbers of facial lesions and their severity were assessed throughout the study. Safety endpoints were also recorded, as were ratings of the cutaneous tolerability (4-point severity scales, investigator- and subject-reported).
Results: The treatment was well tolerated. According to ratings for erythema, scaling/peeling, and edema, none of the subjects experienced worsening of rosacea. Ratings for burning, stinging, tightness, and itching showed that the majority of the subjects improved or were unchanged. Only a single subject reported severe cutaneous irritation at Week 12 (burning, stinging, and itching). Additionally, there were no study-related adverse events or clinically significant changes in laboratory values. Additionally, for both formulations, lesion count and severity were reduced with rapid onset. Clinically meaningful improvements were reported after just four weeks of treatment. The majority of subjects stated they would use the minocycline gel again.
Conclusion: Both formulations of the novel topical minocycline gel demonstrated improvement in treating rosacea and had good cutaneous tolerability profiles. Because cutaneous symptoms such as erythema, edema, burning, and stinging are commonly reported symptoms of rosacea itself, it is to be expected that these were reported with some frequency at baseline. Improvements, which were observed for the majority of subjects in most measures, might therefore be indicative of an improvement in the underlying condition as well as a lack of treatment reaction. Additionally, safety endpoints were met and there was evidence for the effectiveness of treatment in the rapid reduction in number and severity of facial lesions. Although generalizability is limited by the study’s small size and open-label, single-center design, this new therapy shows promise as a new treatment option for rosacea. An important advantage of the topical minocycline formulation might be in reduction of risks associated with systemic exposure to this antibiotic. Next-phase clinical studies are planned.
Efficacy and safety of omalizumab in Japanese and Korean patients with chronic idiopathic/spontaneous urticaria (CIU/CSU): results from the Phase III POLARIS study
Presenters: Hide M1, Park HS 2, Igarashi A3, Ye YM2, Kim TB4, Yagami A5, Roh JY6, Lee JH7, Fukunaga A8, Khalil S9
Affiliations: 1Department of Dermatology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; 2Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea; 3Department of Dermatology, NTT Medical Center Tokyo, Tokyo, Japan; 4Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 5Department of Allergology, Fujita Health University Second Educational Hospital, Nagoya, Japan; 6Department of Dermatology, Gachon University Gil Medical Center, Incheon, Korea; 7Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea; 8Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan; 9Novartis Pharma AG, Basel, Switzerland
Background/Objective: To date, the effect of omalizumab treatment on CIU/CSU has not been extensively assessed in an Asian population. POLARIS represents the first randomized, double-blind, placebo-controlled clinical trial of omalizumab for CIU/CSU in an Eastern Asian population.
Methods: Efficacy and safety of omalizumab as add-on therapy for treatment of CIU/CSU were evaluated in patients aged 12 to 75 years who were refractory to approved doses of nonsedating H1 antihistamines. This 26-week study comprised a two-week screening, 12-week randomized treatment, and 12-week follow up epochs. Patients (n=218) were randomized 1:1:1 to omalizumab 300mg, 150mg, or placebo by subcutaneous injection every four weeks. Primary outcome was changed from baseline (BL) to Week 12 (W12) in weekly itch severity score (ISS7). Secondary endpoints included change from BL in weekly urticaria activity score (UAS7) and weekly number of hives score (HSS7), proportion of patients achieving a UAS7 score between 0 and 6, and change in the Dermatology Life Quality Index (DLQI). Safety was assessed through the summary of adverse events (AEs).
Results: Most disease characteristics were well balanced across treatment arms. At W12, statistically significant decreases were observed from BL in ISS7 with omalizumab versus placebo (mean changes -10.22 and -8.80 for omalizumab 300mg and 150mg; p<0.001 and p=0.006 vs. placebo [-6.51], respectively). The corresponding mean changes from BL in UAS7 were -22.44 and -18.79 (p<0.001 and p=0.007 vs. placebo [?13.90], respectively). At W12, the proportions of patients treated with omalizumab 300mg or 150mg who achieved UAS7 scores of 6 or less were 57.5 percent and 42.9 percent (p<0.001 and p=0.002 vs. placebo [18.9%]), and for UAS7=0 were 35.6 percent and 18.6 percent (p<0.001 and p=0.013 vs. placebo [4.1%]), respectively. Mean changes in HSS7 at W12 were -12.17 and -10.04 with omalizumab 300mg and 150mg (p<0.001 and p=0.016 vs. placebo [-7.41]), respectively. Mean DLQI changes at W12 from BL were -8.4 and -7.2 with omalizumab 300mg and 150mg (p<0.001 and p=0.011 vs. placebo [-5.3]), respectively. Overall incidence of AEs was similar across treatment arms (54.8%, 57.7%, and 55.4% of subjects with omalizumab 300mg, 150mg, and placebo, respectively). Nasopharyngitis was the most frequently reported AE with all treatments.
Conclusion: POLARIS demonstrated that omalizumab treatment results in significant clinical benefits with no new safety concerns in patients with H1 antihistamine-refractory CIU/CSU in Japan and Korea.
Mark your calendars!
Maui Derm for Dermatologists 2019
January 26–30, 2019