University of California, San Diego, School of Medicine, La Jolla, CA, USA; 2

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1 2194 Long-term (104-Week) Efficacy and Safety Profile of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients With Psoriatic Arthritis: Results From a Phase III, Randomized, Controlled Trial and Open-Label Extension () Arthur Kavanaugh 1 ; Adewale O. Adebajo 2 ; Dafna D. Gladman 3 ; Juan J. Gomez-Reino 4 ; Stephen Hall 5 ; Eric Lespessailles 6 ; Philip J. Mease 7 ; Georg Schett 8 ; Kamal Shah 9 ; ChiaChi Hu 9 ; Jürgen Wollenhaupt 10 1 University of California, San Diego, School of Medicine, La Jolla, CA, USA; 2 University of Sheffield, Sheffield, UK; 3 Toronto Western Research Institute, Toronto, ON, Canada; 4 Hospital Clinico Universitario, Santiago, Spain; 5 Monash University, Melbourne, Australia; 6 University of Orléans, Orléans, France; 7 Swedish Medical Center and University of Washington School of Medicine, Seattle, WA, USA; 8 University of Erlangen-Nuremberg, Erlangen, Germany; 9 Celgene Corporation, Warren, NJ, USA; 10 Schön Klinik Hamburg Eilbek, Hamburg, Germany Presented at: the Summer Academy Meeting of the American Academy of Dermatology; August 19 23, 2015; New York, NY. This study was sponsored by Celgene Corporation.

2 Disclosures Dr Arthur F. Kavanaugh has served as an investigator for AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, and UCB. Adewale O. Adebajo has no relevant financial relationships to disclose. Dr Dafna D. Gladman has received research grants and consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB. Dr Juan J. Gomez-Reino has served as an advisory board member for Bristol-Myers Squibb, Pfizer, Roche, Schering-Plough, and UCB SA; as a speaker for Bristol-Myers Squibb, Roche, Schering-Plough, and Wyeth; and has received grant/research support from Roche and Schering- Plough. Dr Stephen Hall has no relevant financial relationships to disclose. Dr Eric Lespessailles has received speaker consultant fees from AMGEN (France) and ELI LILLY (France) and speaker fees from Expancience, Novartis, Servier. Dr Philip J. Mease has received grant/research support from AbbVie, Amgen, Biogen-Idec, Bristol- Myers Squibb, Celgene, Genentech, Janssen, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, and UCB; as a speaker for AbbVie, Amgen, Biogen-Idec, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Lilly, Pfizer, and UCB. Dr Georg Schett has received grant/research support from Celgene and consulting fees from Abbott, Celgene, Roche, and UCB. Dr Kamal Shah and Ms ChiaChi Hu are employees of Celgene Corporation. Jürgen Wollenhaupt has received consulting fees from Abbott, Bristol-Myers Squibb, MSD, Pfizer, and UCB and has received consultation and/or speaking honoraria from Abbott, Amgen, BMS, Chugai, MSD, Medac, Pfizer, Roche, Sanofi-Aventis, and UCB.

3 Abstract Purpose: compared apremilast (APR) efficacy/safety with placebo in patients with active PsA despite prior conventional DMARDs and/or biologics. We report APR efficacy/safety over 104 weeks. Methods: Patients were randomized (1:1:1) to placebo, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). Patients whose SJC/TJC had not improved 20% at Week 16 were considered non-responders and required to be re-randomized (1:1) to APR20 or APR30 (placebo patients), or continued on their initial dose (APR patients). At Week 24, all remaining placebo patients were re-randomized to APR20 or APR30. Double-blind APR treatment continued to Week 52; patients could continue APR 4 additional years. Results: 504 patients received 1 dose of placebo (n=168), APR20 (n=168), or APR30 (n=168). At Week 52, 63.0% (APR20) and 54.6% (APR30) of patients achieved modified ACR20 responses; 80% (285/344) completing Week 52 were still receiving APR at data cutoff during year 2. At Week 104, APR patients demonstrated sustained improvements in modified ACR20/ACR50/ACR70 response (APR20: 60.9%/32.4%/ 16.5%; APR30: 65.3%/34.0%/19.6%); SJC/TJC mean percent change (APR20: 67.6%/-67.1%; APR30: -77.3%/-71.0%); HAQ-DI mean change (APR20: -0.31; APR30: -0.41); DAS-28 (CRP) mean change (APR20: -1.64; APR30: -1.84); DAS-28 (CRP) <2.6 achievement (APR20: 32.9%; APR30: 38.9%); and PASI-75/PASI-50 response (APR20: 31.6%/52.6%; APR30: 29.6%/54.9%). No new safety concerns occurred through Week 104. Nasopharyngitis and URTI occurred in 5% of APR-exposed patients (Weeks >52 104); most AEs were mild/moderate with no long-term increase in incidence/severity. Diarrhea/nausea rates were lower in Weeks > (1.7%/1.2%) vs. Weeks 0 52 (15.3%/12.4%). SAEs occurred in 6.4% (APR20) and 4.1% (APR30) (Weeks >52 104). Fewer discontinuations due to AEs occurred during Weeks > (1.5%) vs. Weeks 0 52 (8.2%). Conclusion: Over 104 weeks, APR demonstrated sustained, clinically meaningful improvements in PsA signs/symptoms, physical function, and psoriasis; had an acceptable safety profile; and was generally welltolerated.

4 Introduction Psoriatic arthritis (PsA) is a chronic systemic inflammatory disease that has multiple signs and symptoms, including inflamed joints and entheses, as well as psoriasis, and can lead to reduced physical function and quality of life for patients. 1-3 PsA onset typically occurs between 30 to 50 years of age and is prevalent in an estimated 0.3% to 1.0% of the general population. 4 The chronic nature of the disease leads to the need for long-term treatment that affects multiple manifestations and improves quality of life. Apremilast is an oral phosphodiesterase 4 inhibitor that works intracellularly to regulate inflammatory mediators associated with the pathogenesis of PsA. 5 The efficacy and safety of apremilast are being evaluated in patients with active PsA in the Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial program. compared the efficacy and safety of apremilast with placebo in patients with active PsA despite prior conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or biologics. This report presents the long-term efficacy and safety of apremilast in patients treated for up to 2 years in the study. 1. Singh JA, et al. J Rheumatol. 2009;36: Tillett W, et al. Rheumatology (Oxford). 2012;51: Lloyd P, et al. Arthritis. 2012;2012: Schafer P. Biochem Pharmacol. 2012;83:

5 : Study Design Placebo-Controlled Phase Blinded Active Treatment Phase Long-term Open-Label Phase Week 4 Baseline Week 4 Week 16 Week 24 Week 52 5 Years Apremilast 30 mg BID Apremilast 30 mg BID Apremilast 30 mg BID SCREEN RANDOMIZE* 1:1:1 Placebo Early Escape Re-randomize Stratify by DMARD use Apremilast 20 mg BID Apremilast 20 mg BID Apremilast 20 mg BID Primary End Point: ACR20 at Week 16 *All doses were titrated over the first week of treatment. Patients whose swollen joint count and tender joint count had not improved by 20% at Week 16 were considered non-responders and were required to be re-randomized (1:1) to apremilast 30 mg BID or 20 mg BID if they were initially randomized to placebo. Apremilast-treated patients remained on their initial dose. At Week 24, all remaining placebo patients were re-randomized to apremilast 30 mg BID or 20 mg BID.

6 Efficacy assessments made over 104 weeks Modified American College of Rheumatology 20 (ACR20) response, ACR50 response, and ACR70 response. The modified ACR20 response requires 20% improvement from baseline (defined as the last non-missing value before the first dose of study medication) in Swollen Joint Count (SJC) and Tender Joint Count (TJC). These counts are based on evaluation of 76 swollen and 78 tender joints which can be assessed for swelling, and 78 which can be assessed for tenderness; joints are those which may be affected by Psoriatic Arthritis. In addition, 20% improvement in 3 of the following: patient s global assessment of disease activity (0-100 mm visual analog scale [VAS]); physician s global assessment of disease activity (VAS); patient s assessment of pain (VAS); Health Assessment Questionnaire- Disability Index (HAQ-DI); or C-reactive protein (CRP) level. 1 Similarly, modified ACR50 and ACR70 responses require 50% and 70% improvements, respectively, in SJC and TJC, plus the corresponding percentage improvements in 3 of the measures described above. 1. Felson DT, et al. Arthritis Rheum. 1995;38:

7 Efficacy assessments made over 104 weeks Mean percent change from baseline in SJC and TJC. Mean change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI). This disability index measures levels of difficulty in performing tasks of daily living; the score ranges from 0-3 for an individual patient. Proportion of patients meeting one of the minimal clinically important difference definitions (MCID), a change of 0.30, in the HAQ-DI. 1 Although an estimated MCID level for the HAQ-DI of 0.35 was subsequently published, 2 this was not available at the time of protocol development and is not included in the current analyses. Mean change from baseline in the Disease Activity Score-28 Joint count (DAS- 28), a composite measure of disease activity including SJC and TJC of 28 joints, CRP or ESR, and patient's global disease activity. Scores range from Proportion of patients achieving a DAS-28 (CRP) score <2.6, which is a measure of disease remission. 3 Proportion of patients with baseline psoriasis body surface area (BSA) involvement 3% who achieved 50% or 75% reductions from the baseline Psoriasis Area and Severity Index scores (PASI-50 and PASI-75, respectively). 1. Mease PJ, et al. [abstract SAT0015]. Ann Rheum Dis. 2004;63 (Suppl 1): Mease PJ, et al. J Rheumatol. 2011;38: Saber TP, et al. Arthritis Res Ther. 2010;12:R94.

8 Patient Disposition During the Second Year of Apremilast Exposure Discontinued, n=27 Adverse event 3 Lack of efficacy 10 Non-compliance 2 Withdrawal by patient 9 Death 1 Lost to follow-up 1 Other 1 Apremilast Patients as Treated A total of 504 patients were randomized to placebo (n=168), apremilast 30 mg BID (n=168), and apremilast 20 mg BID (n=168). In all, 154 of the patients initially receiving placebo were re-randomized at Week 16 or Week 24 to apremilast 30 mg BID (n=77) or apremilast 20 mg BID (n=77). Among 344 patients who completed 52 weeks of apremilast treatment and had 1 dose of apremilast in the second year, a total of 285 patients (>80%) continued to receive apremilast at the time of the data cutoff (February 14, 2014). At this point, all patients remaining in the study had completed their Week 104 study visit. Patients treated with apremilast 30 mg BID (Weeks 0-52)* n=245 Patients completing 52 weeks and entering into the next year n=171/245 (69.8%) Ongoing at data cutoff n=144/171 (84.2%) Patients treated with apremilast 20 mg BID (Weeks 0-52)* n=245 Patients completing 52 weeks and entering into the next year n=173/245 (70.6%) Ongoing at data cutoff n=141/173 (81.5%) *Includes all patients regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). Discontinued, n=32 Adverse event 2 Lack of efficacy 11 Withdrawal by patient 14 Lost to follow-up 3 Other 2

9 Baseline Patient Demographics and Clinical Characteristics by Treatment Group Placebo Apremilast 30 mg BID 20 mg BID n=168 n=168 n=168 Age, mean, years Body mass index, mean, kg/m Duration of PsA, mean, years Swollen joint count (0-76), mean Tender joint count (0-78), mean Health Assessment Questionnaire-Disability Index (0-3), mean Disease activity score 28 (C-reactive protein), mean Duration of psoriasis, mean, years PASI score* (0-72), mean Prior use of conventional DMARDs (biologic-naïve), n (%) 120 (71.4) 124 (73.8) 129 (76.8) Prior use of TNF blocker, n (%) 39 (23.2) 37 (22.0) 33 (19.6) Prior biologic failures, n (%) 19 (11.3) 14 (8.3) 14 (8.3) Baseline DMARD use, n (%) 110 (65.5) 106 (63.1) 111 (66.1) Methotrexate (mean dose, 16.6 mg/week) 90 (53.6) 88 (52.4) 95 (56.5) Leflunomide (mean dose, 17.2 mg/day) 11 (6.5) 9 (5.4) 10 (6.0) Sulfasalazine (mean dose, 2.3 g/day) 18 (10.7) 20 (11.9) 16 (9.5) Baseline oral corticosteroid use, n (%) 12 (7.1) 16 (9.5) 25 (14.9) Oral corticosteroid dose, mean (SD), mg/day 6.0 (2.5) 6.1 (2.2) 6.1 (2.9) Baseline NSAID use, n (%) 118 (70.2) 120 (71.4) 123 (73.2) Note: The n reflects the number of randomized patients who received 1 dose of study medication; actual number of patients available for each parameter may vary. *Examined among patients with psoriasis involvement of BSA 3% at baseline and non-missing PASI score at baseline (placebo: n=65; apremilast 30 mg BID: n=82; apremilast 20 mg BID: n=76). All converted to oral prednisone dose. PASI, psoriasis area severity index; DMARD, disease-modifying anti-rheumatic drug; NSAID, non-steroidal anti-inflammatory drug; TNF, tumor necrosis factor.

10 ACR20, ACR50, and ACR70 Responses At Week 52, a modified ACR20 response was achieved by 53.2% (101/190) of patients receiving apremilast 30 mg BID and 59.6% (109/183) of patients receiving apremilast 20 mg BID. Corresponding modified ACR50 and ACR70 response rates were 25.7% (49/191) and 14.1% (27/191) with apremilast 30 mg BID, and 25.0% (45/180) and 11.7% (21/179) with apremilast 20 mg BID, respectively. The modified ACR20, ACR50, and ACR70 response rates were sustained through Week 104 with continued apremilast treatment.

11 ACR20 Response over 104 Weeks ACR20 80 Patients Achieving an ACR20 Response (%) Apremilast 20 mg BID Apremilast 30 mg BID % 60.9% Study Week Apremilast 20 mg BID, n/m 109/183 89/167 85/161 88/148 84/138 Apremilast 30 mg BID, n/m 101/190 96/166 92/159 98/150 94/144 Analyses include all patient data, including the placebo-controlled period, regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). Denominators vary slightly due to availability of sufficient data for each level of ACR response assessment. n/m=number of responders/number of patients with sufficient data for evaluation.

12 ACR50 Response Over 104 Weeks Patients Achieving an ACR50 Response (%) ACR50 80 Apremilast 20 mg BID Apremilast 30 mg BID Study Week 34.0% 32.4% Apremilast 20 mg BID, n/m 45/180 44/166 47/159 47/151 45/139 Apremilast 30 mg BID, n/m 49/191 56/168 49/160 50/150 49/144 Analyses include all patient data, including the placebo-controlled period, regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). Denominators vary slightly due to availability of sufficient data for each level of ACR response assessment. n/m=number of responders/number of patients with sufficient data for evaluation.

13 ACR70 Response Over 104 Weeks Patients Achieving an ACR70 Response (%) ACR70 Apremilast 20 mg BID Apremilast 30 mg BID Study Week 19.6% 16.5% Apremilast 20 mg BID, n/m 21/179 25/168 26/156 22/151 23/139 Apremilast 30 mg BID, n/m 27/191 33/169 26/161 32/152 28/143 Analyses include all patient data, including the placebo-controlled period, regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). Denominators vary slightly due to availability of sufficient data for each level of ACR response assessment. n/m=number of responders/number of patients with sufficient data for evaluation.

14 Swollen Joint Count and Tender Joint Count Results At Week 52, mean percent reductions from baseline in SJC and TJC were 50.5% and 45.1%, respectively, among patients receiving apremilast 30 mg BID and 61.8% and 59.9%, respectively, among patients receiving apremilast 20 mg BID. Mean reductions from baseline in SJC and TJC observed at Week 52 were sustained through Week 104 with continued apremilast treatment.

15 Change in Swollen Joint Count and Tender Joint Count Over 104 Weeks Mean % Change From Baseline Change From Baseline in Swollen Joint Count Study Week Apremilast 20 mg BID Apremilast 30 mg BID -100 Apremilast 20 mg BID, n Apremilast 30 mg BID, n Mean % Change From Baseline Change From Baseline in Tender Joint Count Study Week Apremilast 20 mg BID Apremilast 30 mg BID Apremilast 20 mg BID, n Apremilast 30 mg BID, n Analyses include all patient data, including the placebo-controlled period, regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). 67.6% 77.3% 67.1% 71.0%

16 Health Assessment Questionnaire Disability Index At Week 52, mean improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) score was 0.31 in patients receiving apremilast 30 mg BID and 0.33 in patients receiving apremilast 20 mg BID. Mean improvement in HAQ-DI score at Week 52 was sustained through Week 104 with continued apremilast treatment. The proportion of patients who achieved HAQ-DI improvement 0.30 was sustained from Week 52 to Week 104.

17 Change From Baseline in HAQ-DI Score Over 104 Weeks Mean Change From Baseline Patients Achieving HAQ-DI MCID 0.30 (%) Change From Baseline in HAQ-DI Score Study Week Apremilast 20 mg BID Apremilast 30 mg BID Apremilast 20 mg BID, n Apremilast 30 mg BID, n Proportion of Patients Achieving HAQ-DI MCID 0.3* 40 Apremilast 20 mg BID 20 Apremilast 30 mg BID Study Week Apremilast 20 mg BID, n/m 84/184 70/172 69/162 69/153 70/142 Apremilast 30 mg BID, n/m 85/193 86/169 83/161 77/153 78/ % 49.3% Analyses include all patient data, including the placebo-controlled period, regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). *Prespecified thresholds for MCID based on the literature at the time of protocol development (Mease PJ, et al. Abstract SAT0015. Ann Rheum Dis. 2004;63(Suppl 1):391). An estimated MCID for the HAQ-DI of 0.35 was subsequently published (Mease PJ, et al. J Rheumatol. 2011;38: ) but was not available at the time of protocol development and is not included in the current analyses. n/m=number of responders/number of patients with sufficient data for evaluation; MCID, minimal clinically important difference

18 Disease Activity Score 28 (C-reactive protein) Over 104 Weeks Improvements in Disease Activity Score 28 (C-reactive protein) (DAS-28 [CRP]) were sustained from Week 52 to Week 104 with continued apremilast treatment. At Week 104, 38.9% of patients receiving apremilast 30 mg BID and 32.9% of patients receiving apremilast 20 mg BID achieved remission, as defined by a DAS-28 (CRP) <2.6.

19 Disease Activity Score 28 (C-reactive protein) Over 104 Weeks Mean Change From Baseline Change From Baseline in DAS-28 (CRP) Study Week Apremilast 20 mg BID Apremilast 30 mg BID Apremilast 20 mg BID, n Apremilast 30 mg BID, n Patients Achieving DAS <2.6 (%) Proportion of Patients Achieving Remission, as Defined by DAS-28 (CRP) < Apremilast 20 mg BID Apremilast 30 mg BID Study Week Apremilast 20 mg BID, n/m 56/185 58/171 53/161 49/153 47/143 Apremilast 30 mg BID, n/m 41/189 49/167 50/158 53/152 56/144 Analyses include all patient data, including the placebo-controlled period, regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). n/m=number of responders/number of patients with sufficient data for evaluation % 32.9%

20 PASI-50 and PASI-75 Response Over 104 Weeks Among Patients With Psoriasis BSA 3% at Baseline Patients Achieving a PASI-50 Response (%) PASI-50 Apremilast 20 mg BID Apremilast 30 mg BID Study Week Apremilast 20 mg BID, n/m 39/78 38/73 39/67 35/62 30/57 Apremilast 30 mg BID, n/m 52/95 44/78 39/75 38/72 39/ % 52.6% Patients Achieving a PASI-75 Response (%) PASI-75 Apremilast 20 mg BID Apremilast 30 mg BID Study Week Apremilast 20 mg BID, n/m 17/78 17/73 20/67 22/62 18/57 Apremilast 30 mg BID, n/m 31/95 17/78 20/75 19/72 21/71 Analyses include all patient data, including the placebo-controlled period, regardless of when patients started taking apremilast (baseline, Week 16, or Week 24). n/m=number of responders/number of patients with sufficient data for evaluation. 31.6% 29.6%

21 Overview of Adverse Events Most adverse events (AEs) were mild or moderate in severity in both the Weeks 0 to 52 and Weeks >52 to 104 apremilast-exposure periods; in general, no increase was seen in the incidence or severity of AEs with longer-term exposure During the Weeks >52 to 104 apremilast-exposure period, diarrhea and nausea occurred at lower rates (1.7% and 1.2%, respectively) than during the Weeks 0 to 52 apremilastexposure period (15.3% and 12.4%, respectively). Discontinuations due to AEs occurred at a lower rate during the Weeks >52 to 104 apremilast-exposure period (1.5%) than during the Weeks 0 to 52 apremilast-exposure period (8.2%). Gastrointestinal (GI) AEs leading to apremilast discontinuation occurred at low rates and were mostly seen early during treatment with apremilast. During the Weeks >52 to 104 apremilast-exposure period, only 1 patient (0.3%) discontinued apremilast due to a GI AE (diarrhea). No cases of tuberculosis (new or reactivation) were reported with either apremilast dose over 104 weeks. One death occurred during the Weeks >52 to 104 apremilast-exposure period; it was unrelated to the treatment (motor vehicle accident). Marked laboratory abnormalities were generally infrequent and returned to baseline with continued treatment. No new safety concerns were observed during long-term exposure to apremilast from Week 52 to Week 104.

22 Overview of Adverse Events Apremilast-Exposure Period* Weeks 0 to mg BID n=245 Apremilast 20 mg BID n=245 Apremilast-Exposure Period* Weeks >52 to mg BID n=171 Apremilast 20 mg BID n=173 Patients, n (%) 1 AE 178 (72.7) 171 (69.8) 101 (59.1) 108 (62.4) 1 serious AE 21 (8.6) 14 (5.7) 8 (4.7) 11 (6.4) 1 serious infection 3 (1.2) 2 (0.8) 1 (0.6) 2 (1.2) AE leading to drug withdrawal 23 (9.4) 17 (6.9) 3 (1.8) 2 (1.2) Death 0 1 (0.4) 1 (0.6) 0 AEs in 5% of patients, any treatment group, n (%) Diarrhea 47 (19.2) 28 (11.4) 3 (1.8) 3 (1.7) Nausea 37 (15.1) 24 (9.8) 1 (0.6) 3 (1.7) Headache 24 (9.8) 22 (8.2) 8 (4.7) 6 (3.5) Upper respiratory tract infection 15 (6.1) 20 (8.2) 8 (4.7) 15 (8.7) Nasopharyngitis 16 (6.5) 18 (7.3) 12 (7.0) 7 (4.0) *Includes all patients who received apremilast during the time interval relative to the start of apremilast administration. Multiorgan failure; not suspected to be treatment-related. Motor vehicle accident on Study Day 489.

23 Conclusions Apremilast 30 mg BID and 20 mg BID demonstrated sustained and clinically meaningful improvements in the signs and symptoms of PsA, including tender and swollen joints, physical function, and psoriasis for up to 104 weeks of continued apremilast treatment. Improvements in efficacy measures observed at Week 52 were sustained during continued treatment with apremilast to Week 104. Apremilast continued to demonstrate an acceptable safety profile and was generally well tolerated for up to 104 weeks. No new safety concerns were identified during longer-term exposure to apremilast.

Abstract Background: Methods: Results: Conclusion:

Abstract Background: Methods: Results: Conclusion: 1131 Efficacy of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, for Palmoplantar Psoriasis in Patients With Moderate to Severe Plaque Psoriasis in Phase 2 and Phase 3 (ESTEEM) Trials Robert Bissonnette,