Adalimumab for Nail Psoriasis: Efficacy and Safety from the Open-Label Extension of a Phase-3, Randomized, Placebo-Controlled Trial Alice B Gottlieb1, Boni E Elewski2, Martin M Okun3, Jerry Bagel4, Yves Poulin5, Yihua Gu6, Ziqian Geng6, David A Williams6, Wendell C Valdecantos6 1 New York Medical College, Valhalla, NY, USA; 2University of Alabama at Birmingham, School of Medicine, Birmingham, AL, USA; 3Fort HealthCare, Fort Atkinson, WI, USA; 4University Medical Center of Princeton at Plainsboro, Plainsboro, NJ, USA; 5Centre Dermatologique du Québec Métropolitain, Québec, QC, Canada; 6AbbVie Inc, North Chicago, IL, USA INTRODUCTION Presented at the Fall Clinical Dermatology Conference - 36th Anniversary • Las Vega, Nevada • October 12 – 15, 2017 METHODS RESULTS • Treatments that are simultaneously effective in nail and skin psoriasis are needed as affected patients have worse quality of life and pain than patients with skin psoriasis alone. • Management of nail psoriasis is challenging; the disease etiology and pathology are not fully understood and treatment guidelines are limited.1,2 Topical agents have been minimally effective, but improvement in nail psoriasis has been reported following treatment of skin psoriasis with biologic therapies.3 • We evaluated the safety and efficacy of originator adalimumab (AbbVie) for fingernail psoriasis in the open-label-extension period (Period B) of a phase-3 trial of adalimumab (ADA) in patients with moderate-to-severe psoriasis who also had substantial, clinically impactful, moderate-to-severe fingernail psoriasis (clinicaltrials.gov NCT 02016482). 1. Crowley JJ, et al. JAMA Dermatol. 2015;151:87-94. 2. Langley RG, et al. J Eur Acad Dermatol Venereol. 2012;26:373-81. 3. Pasch MC. Drugs. 2016;76:675-705. 4. Cassell SE, et al. J Rheum. 2007;34:1239. 5. Rich P, et al. J Am Acad Dermatol. 2003;49:206-12. REFERENCES • For psoriasis patients with concomitant nail disease who received 40 mg ADA every-other-week treatment for 26 weeks in Period A, treatment response was maintained from entry to Period B through week 52. • Patients receiving PBO in Period A, who switched to 40 mg ADA every-other-week treatment in Period B, eventually reached a similar response at week 52, to those receiving continuous ADA treatment. • No new safety risks were identified with 40 mg ADA every-other- week treatment for 52 weeks. CONCLUSIONS A Gottlieb received fees for serving on advisory boards and for consulting services from Amgen Inc.; Astellas, Akros, Centocor (Janssen), Inc.; Celgene Corp., Bristol Myers Squibb Co., Beiersdorf, Inc., Abbott Labs. (Abbvie), TEVA, Actelion, UCB, Novo Nordisk, Novartis, Dermipsor Ltd., Incyte, Pfizer, Canfite, Lilly, Coronado, Vertex, Karyopharm, CSL Behring Biotherapies for Life, Glaxo Smith Kline, Xenoport, Catabasis, Meiji Seika Pharma Co., Ltd, Takeda, Mitsubishi,Tanabe Pharma Development America, Inc, Genentech, Baxalta, Kineta One, KPI Therapeutics, Crescendo Bioscience, Aclaris, Amicus, Reddy Labs, Valeant, Dermira, Allergan. BE Elewski received research funding for clinical research support, paid to her affiliation, from Abbvie, Amgen, Boehringer Ingelheim, Celgene, Incyte, Lilly, Merck, Novan, Novartis, Pfizer, Valeant, and Viamet; received honoraria for consultant services from Anacor, Celgene, Lilly, Novartis, Pfizer, and Valeant. MM Okun received honoraria from AbbVie for advisory board participation and speaker services, and from AbbVie, Gilead Science, and Crescendo Biosciences for consultant services. Dr. Okun was an AbbVie employee during this study and is currently affiliated with Fort HealthCare, Fort Atkinson, WI, USA. J Bagel received honoraria or grants for speaker, consultant, or investigator services with Abbvie, Boehringer Ingelheim, Celgene, Eli-Lilly, Janssen, Leo Pharma, Novartis, and Sun Valiant. Y Poulin received grants for investigator services with AbbVie, Amgen, Baxalta, Celgene, Centocor, Janssen, Eli Lilly, Glaxo Smith Kline, Incyte, Leo Pharma, Merck, Novartis, Pfizer, and UCB Pharma, and received honoraria for speaker and/ or advisory board services for AbbVie, Amgen, Janssen, and Leo Pharma. Y Gu, Z Geng, D Williams, W Valdecantos receive a salary as AbbVie employees, and may also receive AbbVie stocks or stock options. AbbVie Inc. funded this study and participated in the study design; study research; collection, analysis and interpretation of data; and writing, reviewing and approving of this publication. All authors had access to the data, and participated in the development, review, and approval, and in the decision to submit this publication. The authors would like to acknowledge Jody Bennett, employed by AbbVie, for medical writing support in the production of this publication. DISCLOSURES & ACKNOWLEDGEMENTS • Patients with chronic, moderate-to-severe plaque psoriasis and fingernail psoriasis were enrolled. In 26-week Period A, patients were randomized 1:1 to 40 mg ADA every-other-week (ADAeow) after initial 80 mg dose, or matching placebo (PBO). • From week 16, if the affected body surface area increased by ≥25% from baseline, patients were required to roll over to the 26-week Period B (early escape). Patients completing Period A at week 26 or who escaped early, entered Period B at week 26. • At Period B entry (week 26), patients receiving PBO in Period A received an initial blinded dose of 80 mg ADA; patients receiving ADA in Period A received matching PBO. All received 40 mg ADAeow from weeks 27 through 51 (Figure 1). Figure 1. Study Design ADA 40 mg eow PBO Period A Double-blind 26 weeks Period B Open-label extension (OLE) 26 weeks Screening 3-35 days Week 0 a Week 16 b Week 26c Week 52 1:1 randomiza�on aInitial dose of ADA was 80 mg. bStarting at week 16, if psoriasis-affected BSA increased ≥25% over baseline, patients were rolled over to Period B. cPeriod-A ADA arm received matching PBO; Period-A PBO arm received blinded ADA 80 mg. Abbreviations: ADA=adalimumab; eow=every-other-week dosing; PBO=placebo; BSA=body surface area. KEY INCLUSION CRITERIA • Adults diagnosed with both chronic, moderate-to-severe plaque psoriasis (with disease duration of at least 6 months) and moderate- to-severe psoriasis in at least one fingernail (any disease duration). • BSA ≥10% and baseline target fingernail modified Nail Psoriasis Severity Index (mNAPSI)4 ≥8; or BSA ≥5% with baseline target fingernail mNAPSI ≥8 and baseline total mNAPSI ≥20 (scale of total score 0 [no nail findings] to 130 [nail findings present in each nail]). • Physician’s Global Assessment of Fingernail (PGA-F) of at least moderate severity for fingernail psoriasis (scale 0 [clear] to 4 [severe]). • Nail Psoriasis Physical Functioning Severity (NPPFS) score >3 (scale 0 [none] to 10 [severe]); or Nail Psoriasis Pain Numeric Rating Scale (NRS) score >3 (scale 0 [no pain] to 10 [severe pain]). ENDPOINTS • All efficacy variables assessed in Period A were also assessed in Period B (see list in Table 3). Period A primary and ranked secondary endpoints that were evaluated in Period B are reported here. • Two intent-to-treat (ITT) patient populations were evaluated in Period B: – Overall ITT_B Population: all patients who received ≥1 study drug injection in Period B. – Early Escape Population: all patients who rolled over to Period B after experiencing worsening of disease from baseline in Period A. • Period B treatment groups are identified by treatment received in Period A/Period B, ie, PBO/ADA and ADA/ADA. • Missing data were handled in Period A by multiple imputation (MI), and in Period B by non-responder imputation (NRI) and by last observation carried forward (LOCF). SAFETY • Treatment-emergent adverse events (AEs) in Period B were analyzed for the ITT_B Population. • 217 patients were randomized in Period A (108 to PBO; 109 to ADA). – 94/108 (87.0%) PBO/ADA and 94/109 (86.2%) ADA/ADA entered Period B (Table 1). – 81/94 (86.2%) PBO/ADA and 87/94 (92.6%) ADA/ADA patients completed Period B. Table 1. Patient Disposition, Period B Disposition, n (%) PBO/ADA, N=94 ADA/ADA, N=94 n % n % Entered Period B 94 100 94 100 Completed Period B 81 86.2 87 92.6 Discontinued Period B; primary reason: 13 13.8 7 7.4 Adverse events 0 0 0 0 Withdrew consent 1 1.1 1 1.1 Lost to follow-up 2 2.1 0 Lack of efficacy 6 6.4 4 4.3 All other reasonsa 4 4.3 2 2.1 aIncludes requirement for alternate therapy, and other reasons. • Demographic and baseline characteristics were generally comparable across the 2 treatment groups (Table 2). Patients showed substantial nail disease and pain at baseline. Table 2. Key Demographics and Baseline Characteristics of Patients Entering Period B Characteristic PBO/ADA, N=94 ADA/ADA, N=94 N % N % Sex Male 76 80.9 83 88.3 Female 18 19.1 11 11.7 Race White 90 95.7 89 94.7 Asian 3 3.2 4 4.3 Othera 1 1.1 1 1.1 BSA 5% to <10% 34 36.2 37 39.4 ≥10% 60 63.8 57 60.6 Scalp psoriasis 80 85.1 80 85.1 PsA 26 27.7 28 29.8 PGA-F Moderate 53 56.4 44 46.8 >Moderate 41 43.6 50 53.2 PGA-Sb Moderate 55 58.5 56 59.6 >Moderate 39 41.5 37 39.4 Mean SD Mean SD Age, years 47.1 11.44 47.3 11.82 BMI, kg/m2 (n=93) 29.2 6.88 (n=93) 29.6 5.09 Duration of psoriasis, years 18.7 13.73 20.7 12.34 Duration of nail psoriasis, years 12.0 11.12 12.4 9.65 PASI score 13.3 9.87 12.8 9.00 Total fingernail mNAPSI score (range 0-130) 58.6 20.78 57.0 18.34 Total fingernail NAPSI score (range 0-80) 46.6 15.40 48.0 15.67 Nail Psoriasis Pain (NRS) score (range 0-10) 5.7 2.25 5.0 2.48 B-SNIPI, scalp component (range 0-20) (n=16) 7.9 5.82 (n=23) 9.7 5.32 NPPFS score (range 0-10) 5.2 2.15 5.2 2.63 DLQI score (range 0-30) (n=82) 12.3 6.73 (n=81) 13.0 7.31 Nail Psoriasis QoL score (range 0-10) 5.2 2.28 4.9 2.79 aOther includes Black (ADA/ADA) and multi-race (PBO/ADA). b1 patient had PGA-S mild. For all scores listed above, higher scores indicate higher disease severity or impairment. Abbreviations: PBO=placebo; ADA=adalimumab; BSA=body surface area; PsA=psoriatic arthritis; BMI=body mass index; PASI=Psoriasis Area Severity Index; PGA=Physician Global Assessment (-F=fingernail psoriasis, -S=skin psoriasis); NAPSI=Nail Psoriasis Severity Index (m=modified); NRS=Numeric Rating Scale; B-SNIPI=Brigham Scalp Nail Inverse Palmo-Plantar Psoriasis Index; NPPFS=Nail Psoriasis Physical Functioning Severity; DLQI=Dermatology Life Quality Index; QoL=quality of life. EFFICACY IN PERIOD A • Results at week 26 are shown in Table 3. All results were statistically significant (P<0.001 for all but B-SNIPI 50 scalp and mNAPSI=0; P<0.01). Table 3. Efficacy Outcomes in Period A PBON=108 ADA, N=109 Primary Endpoint Percent of patients who achieved at least a 75% reduction in total fingernail mNAPSI (mNAPSI 75) relative to baseline 3.4% 46.6% Ranked Secondary Endpoints Mean percent improvement from baseline in total fingernail NAPSI 11.5% 56.2% Percent of patients who achieved total fingernail mNAPSI=0 0% 6.6% Mean improvement from baseline in nail psoriasis pain (NRS; used to capture a patient’s self-report of worst fingernail pain) 1.1 3.7 Mean improvement from baseline in NPPFS 0.8 3.7 Percent of patients who achieved B-SNIPI 50 scalp (at least 50% improvement in the scalp component of the Brigham Scalp Nail Inverse Palmo-Plantar Psoriasis Composite Index, among patients with a baseline scalp score of 6 or greater)a 0.4% 58.3% Percent of patients who achieved PGA-F 0 (clear) or 1 (minimal), with ≥2 grades improvement from baselineb 6.9% 48.9% aMeasured only at US and Puerto Rico sites. bPrimary endpoint in US only, for US regulatory purposes. Abbreviations: PBO=placebo; ADA=adalimumab; NAPSI=Nail Psoriasis Severity Index (m=modified); NRS=numerical rating score; NPPFS=Nail Psoriasis Physical Functioning Severity; PGA-F=Physician’s Global Assessment of fingernail. EFFICACY IN PERIOD B (FIGURE 2A-G) • Overall ITT_B Population: At week 52, response rates for the various efficacy endpoints were maintained for patients who continued ADA in Period B, and improved for patients who switched from PBO in Period A to ADA in Period B. • Early Escape Population: – 188 patients were in the Early Escape Population (94 PBO/ADA; 94 ADA/ADA). – Patients who experienced worsening of disease from baseline in Period A and continued ADA in Period B had less improvement than those who switched from PBO in Period A to ADA in Period B. – Only 8 patients in the ADA/ADA group, vs. 56 in the PBO/ADA group, experienced worsening of disease from baseline in Period A and needed to escape early to Period B. Figure 2. Efficacy Outcomes in Period B for Two Populations ≥ A. Achievement of mNAPSI 75 NRI. Missing at week 52 (n): ITT_B 14 PBO/ADA, 8 ADA/ADA; Early Escape 7 PBO/ADA, 2 ADA/ADA. B. Achievement of PGA-F 0 or 1, with 2 Grades Improvement from Baseline NRI. Missing at week 52 (n): ITT_B 14 PBO/ADA, 8 ADA/ADA; Early Escape 7 PBO/ADA, 2 ADA/ADA. C. Improvement from Baseline in Total Fingernail NAPSI LOCF. D. Achievement of Total Fingernail mNAPSI 0 NRI. Missing at week 52 (n): ITT_B 14 PBO/ADA, 8 ADA/ADA; Early Escape 7 PBO/ADA, 2 ADA/ADA. E. Improvement from Baseline in Pain NRS LOCF. F. Improvement from Baseline in NPPFS LOCF. ITT_B Population PBO/ADA, N=94 ADA/ADA, N=94 Early Escape Population PBO/ADA, N=56 ADA/ADA, N=8 ITT_B Population PBO/ADA, N=94 ADA/ADA, N=94 Early Escape Population PBO/ADA, N=56 ADA/ADA, N=8 ITT_B Population PBO/ADA, N=94 ADA/ADA, N=94 Early Escape Population PBO/ADA, N=56 ADA/ADA, N=8 (Period B Entry); N=6 (Week 52) ITT_B Population PBO/ADA, N=94 ADA/ADA, N=94 Early Escape Population PBO/ADA, N=56 ADA/ADA, N=8 ITT_B Population PBO/ADA, N=94 ADA/ADA, N=94 (Period B Entry); N=93 (Week 52) Early Escape Population PBO/ADA, N=56 ADA/ADA, N=8 Early Escape Population PBO/ADA, N=56 ADA/ADA, N=8 ITT_B Population PBO/ADA, N=94 ADA/ADA, N=94 (Period B Entry); N=93 (Week 52) SAFETY • Approximately half of the patients experienced a treatment-emergent AE in Period B (Table 4). The rates of serious AEs and serious infections were low. There were no AEs of tuberculosis, malignancy, or AEs leading to study-drug discontinuation; and no deaths. Table 4. Safety in Period B Adverse Events (AE), n (%) Period A Period B PBO/ADA N=108 ADA/ADA N=109 PBO/ADA N=94 ADA/ADA N=94 Any AE 61 (56.5) 64 (58.7) 44 (46.8) 47 (50.0) Serious AEs 5 (4.6) 8 (7.3) 3 (3.2) 3 (3.2) Infections 30 (27.8) 32 (29.4) 25 (26.6) 30 (31.9) Serious infectiona 2 (1.9) 4 (3.7) 2 (2.1) 1 (1.1) Tuberculosis 0 0 0 0 Malignancy 0 0 0 0 Leading to study drug discontinuation 3 (2.8) 6 (5.5) 0 0 Death 0 0 0 0 Special interestb AEs Allergic reactionc 2 (1.9) 1 (0.9) 1 (1.1) 0 Worsening/new onset of psoriasis 7 (6.5) 2 (1.8) 4 (4.3) 1 (1.1) Injection-site reaction 3 (2.8) 4 (3.7) 2 (2.1) 2 (2.1) aSerious infections: Period A pneumonia (n=2 PBO), and bronchitis, diverticulitis, endocarditis, erysipelas (n=1 each ADA); Period B influenza (n=1 ADA/ADA), lung infection (n=1, PBO/ADA), and diverticulitis (n=1, PBO/ ADA). bAEs of special interest in <2 patients in a treatment group: Period A oral candidiasis, congestive heart failure, intestinal perforation, and hematologic disorders including pancytopenia (ADA); Period B diverticulitis, myocardial infarction, and hematologic disorders including pancytopenia (PBO/ADA). cIncluded angioedema and anaphylaxis. Abbreviations: PBO=placebo; ADA=adalimumab. G. Achievement of B-SNIPI 50 scalp NRI. Missing at week 52 (n): ITT_B 3 PBO/ADA, 2 ADA/ADA; Early Escape 3 PBO/ADA, 1 ADA/ADA. ITT_B Population PBO/ADA, N=9 ADA/ADA, N=16 Early Escape Population PBO/ADA, N=7 ADA/ADA, N=1 FC17PosterAbbVieGottliebAdalimumabNailPsoriasis.pdf