Toulouse University, Hôpital Larrey, Toulouse, France

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1 2177 Long-term Safety and Tolerability of Apremilast in Patients With Psoriasis: Analysis of Two Phase 3, Randomized, Controlled Trials (ESTEEM 1 and 2) Kristian Reich, MD 1 ; Kim Papp, MD 2 ; Kenneth B. Gordon, MD 3 ; Christopher E.M. Griffiths, MD 4 ; Sergio Chimenti, MD 5 ; Jose Luis Lopez-Estebaranz, MD 6 ; Alice B. Gottlieb, MD, PhD 7 ; Kamal Shah, MD 8 ; ChiaChi Hu, EdM, MS 8 ; Robert M. Day, PhD 8 ; Carle Paul, MD 9 1 SCIderm Research Institute and Dermatologikum Hamburg, Hamburg, Germany; 2 Probity Medical Research, Waterloo, ON, Canada; 3 Northwestern University, Chicago, IL, USA; 4 Dermatology Centre, University of Manchester, Manchester, UK; 5 University of Rome Tor Vergata, Rome, Italy; 6 Hospital Universitario Fundacion Alcorcon, Madrid, Spain; 7 Tufts Medical Center, Boston, MA, USA; 8 Celgene Corporation, Warren, NJ, USA; 9 Toulouse University, Hôpital Larrey, Toulouse, France 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 Kristian Reich has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Biogen-Idec, Celgene, Centocor, Covagen, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Lilly, Medac, MSD, Novartis, Pfizer, Vertex, and Takeda. Dr Kim A. Papp has served as an investigator for Abbott (AbbVie), Amgen, Biogen-Idec, Boehringer Ingelheim, Celgene, Centocor, Galderma, Genentech, Incyte, Isotechnika, Janssen, LEO Pharma, Lilly, MedImmune, Merck Sharp & Dohme, Merck- Serono, Novartis, Stiefel, Pfizer, and Wyeth; a consultant for Abbott, Amgen, Astellas, Biogen-Idec, Boehringer Ingelheim, BMS, Celgene, Centocor, Forward Pharma, Galderma, Genentech, Incyte, Isotechnika, Janssen, Johnson & Johnson, Kyowa Kirin, LEO Pharma, Eli Lilly, MedImmune, Merck Sharp & Dohme, Merck-Serono, Novartis, Pfizer, Takeda Pharmaceuticals, UCB, and Wyeth; and a speaker for Abbott, Amgen, Astellas, Celgene, Centocor, Isotechnika, Janssen, Novartis, and Pfizer. Dr Kenneth Gordon has served as a consultant and investigator for Abbott, Amgen, Centocor, and Merck, and as a consultant for Eli Lilly and Pfizer. Dr Christopher E.M. Griffiths has received honoraria and/or research grants as a consultant, investigator, and/or speaker for AbbVie, Actelion, Amgen, Celgene, Eli Lilly, GlaxoSmithKline, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Trident, Sandoz, and UCB, and is a National Institute for Health Research Senior Investigator. Dr Sergio Chimenti has received honoraria and research grants as an investigator and/or advisory board member for Abbott, Celgene, Janssen, and Pfizer. Dr Jose Luis López-Estebaranz has served as an advisory board member for conferences for AbbVie, Celgene, Janssen, MSD, Novartis, and Pfizer. Dr Alice B. Gottlieb is a consultant and/or advisory board member for Abbott (AbbVie), Actelion, Amgen, Akros, Astellas, Beiersdorf, Bristol-Myers Squibb, Canfite, Catabasis, Celgene, Centocor (Janssen), Coronado, CSL Behring Biotherapies for Life, Dermipsor, DUSA, GlaxoSmithKline, Incyte, Karyopharm, Lilly, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, TEVA, UCB, Vertex, and Xenoport, and is a recipient of research/educational grants paid to Tufts Medical Center by Abbott (AbbVie), Amgen, Celgene, Centocor (Janssen), Coronado, Levia, Lilly, Merck, Novartis, Pfizer, Xenoport, Takeda, and Mitshubishi. Dr Kamal Shah, Ms ChiaChi Hu, and Dr Robert M. Day are employees of Celgene Corporation. Dr Carle F. Paul has served on the advisory board and/or received speaker honoraria for AbbVie, Celgene, Janssen, and Novartis.

3 Abstract Purpose: Overall safety and tolerability of apremilast (APR) in moderate to severe plaque psoriasis were assessed in a pooled analysis of two phase 3 trials (ESTEEM 1 and 2). Methods: Patients (pts) (PASI 12, BSA 10%, spga 3) were randomized (2:1) to APR 30 mg BID (APR30) or placebo (PBO) through Wk 16, after which all pts received APR30 to Wk 32, followed by a randomized treatment withdrawal phase to Wk 52. AEs were assessed for Wks 0 to 16; Wks 0 to 52; and the APR-exposure period through January 11, Results: 1,250 pts received study medication at Wk 0 (PBO: n=418; APR30: n=832); 1,184 received APR30 (968 pts for 24 wks; 564 for 52 wks). Adverse events (AEs) 5% (Wks 0 to 16) in PBO or APR30 pts, respectively, were diarrhea (6.7%, 17.8%), nausea (6.7%, 16.6%), headache (including tension headache; 6.7%, 13.1%), upper respiratory tract infection (6.5%, 8.4%), and nasopharyngitis (6.9%, 7.3%). These were the most frequently reported AEs for all treatment periods. Most AEs were mild or moderate in severity. The incidence of serious AEs was similar for PBO (2.6%) and APR30 (2.0%), and discontinuation rates due to AEs were low (Wks 0 to 16: PBO, 3.8%; APR30, 5.4%). Long-term (uncontrolled) data did not indicate an increase in AEs or discontinuations based on exposure-adjusted incidence rates/100 pt-years. Diarrhea and nausea with APR30 were predominantly mild, with the highest incidence in the first 2 wks of treatment, and reduced incidence after the first month of dosing. In clinical trials, more pts treated with APR30 reported weight loss and depression vs. PBO. Adjudicated events of major adverse cardiac events, malignancies, and serious and opportunistic infections were comparable for PBO and APR30. There were no clinically meaningful changes in laboratory tests. Conclusion: APR30 demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks.

4 Introduction and Objective Psoriasis is a chronic, systemic inflammatory disease that affects 1% to 3% of the world s population. 1-3 Currently available therapies are often compromised by AEs, safety and tolerability issues, and route of administration (injection/infusion vs. oral). 4 Apremilast, an oral PDE4 inhibitor, works intracellularly to regulate inflammatory mediators 5 ; this medication was approved by the FDA in 2014 and by the EC in 2015 for the treatment of psoriasis and psoriatic arthritis. 6,7 ESTEEM is a phase 3 clinical trial program comprising 2 randomized, placebo-controlled studies evaluating the efficacy, safety, and tolerability of apremilast for the treatment of moderate to severe plaque psoriasis. AEs, adverse events; EC, European Commission; ESTEEM, Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis; FDA, US Food and Drug Administration; PDE4, phosphodiesterase Helmick CG, et al. Am J Prev Med. 2014;47: Rachakonda TD, et al. J Am Acad Dermatol. 2014;70: Parisi R, et al. J Invest Dermatol. 2013;133: Schmitt J, et al. Br J Dermatol. 2008;159: Schafer P. Biochem Pharmacol. 2012;83: Otezla [package insert]. Summit, NJ: Celgene Corporation, Otezla (apremilast) summary of product characteristics. Uxbridge, UK: Celgene Europe Ltd.; January 2015.

5 ESTEEM 1 and 2: Study Design Adult patients aged 18 years and older with moderate to severe plaque psoriasis Period A Period B Period C SCREEN Week 0 Week 16 Week 32 Week 52 RANDOMIZE (1:2) * Placebo PASI, Psoriasis Area and Severity Index PASI-75 (EST 1) PASI-50 (EST 2) < PASI-75 < PASI-50 PASI-75 PASI-50 Apremilast 30 mg BID* < PASI-75 < PASI-50 Placebo At time of loss of effect ± topicals, UVB ± topicals, UVB Long-term extension for up to 5 years *Doses of apremilast were titrated during the first week of administration and at Week 16 when placebo patients were switched to apremilast. Patients restarted apremilast at the time of loss of effect vs. baseline (loss of PASI-75, ESTEEM 1; loss of 50% of the PASI improvement obtained at Week 32, ESTEEM 2) but no later than Week 52. Patients initially on placebo or randomized to apremilast 30 mg BID who did not attain PASI-75/PASI-50 were able to add topicals and/or ultraviolet B at Week 32 at the discretion of the investigator.

6 Baseline Patient Demographics and Disease Characteristics ESTEEM 1 and 2 (Pooled) N=1,255 Full Analysis Set Placebo n=419 n=836 Age, mean, years Male, n (%) 294 (70.2) 555 (66.4) Body mass index, mean, kg/m Weight, mean, kg White, n (%) 378 (90.2) 757 (90.6) Duration of plaque psoriasis, mean, years PASI score (0-72), mean PASI >20, n (%) 136 (32.5) 239 (28.6) Body surface area, mean, % Body surface area >20%, n (%) 229 (54.7) 409 (48.9) spga = 4 (severe), n (%) 138 (32.9) 236 (28.2) Prior systemic therapy (conventional and/or biologics), n (%) 223 (53.2) 458 (54.8) Prior conventional systemic therapy, n (%) 155 (37.0) 318 (38.0) Prior biologic therapy, n (%) 124 (29.6) 254 (30.4) The n reflects the number of patients who were randomized; actual number of patients available for each end point may vary. Patients as initially treated. spga, static physician global assessment.

7 Overview of Adverse Events Most AEs were mild to moderate in severity and did not lead to discontinuation. The incidence of serious AEs was low. The exposure-adjusted incidence rate (EAIR) for serious AEs did not increase with longer apremilast exposure, compared with the placebocontrolled period. One death occurred with placebo treatment: a 28-year-old woman with a history of bipolar disorder and depression committed suicide on Day 55. Two deaths occurred with apremilast exposure: A 30-year-old woman with a history of depression and obesity experienced fatal cardiac failure on Day 111 a 69-year-old man with a history of diabetes, hypertension, and hyperlipidemia had a fatal cerebrovascular accident on Day 666 of apremilast exposure Patients Period A (Placebo-Controlled Period) Weeks 0 to 16 Apremilast-Exposure Period Weeks 0 to 52 Placebo n=418; Pt-Yrs=116.5 n=832; Pt-Yrs=236.8 n=1,184; Pt-Yrs=1,127.9 EAIR/100 EAIR/100 EAIR/100 n (%) Pt-Yrs n (%) Pt-Yrs n (%) Pt-Yrs 1 AE 239 (57.2) (68.9) (80.5) serious AE 11 (2.6) (2.0) (5.7) severe AE 15 (3.6) (3.8) (8.2) 8.9 AE leading to drug withdrawal 16 (3.8) (5.4) (8.4) 8.8 The apremilast-exposure period (0 to 52 weeks) included all patients who received apremilast 30 mg BID, regardless of when treatment was initiated. Exposure-adjusted incidence rate per 100 patient-years is defined as 100 the number (n) of patients reporting the event divided by patient-years (up to the first event start date for patients reporting the event).

8 Adverse Events 5% in Any Treatment Group Patients Placebo-Controlled Period Weeks 0 to 16 Placebo n=418; Pt-Yrs=116.5 n (%) EAIR/100 Pt-Yrs n (%) n=832; Pt-Yrs=236.8 EAIR/100 Pt-Yrs n (%) Apremilast-Exposure Period Weeks 0 to 52 n=1,184; Pt-Yrs=1,127.9 EAIR/100 Pt-Yrs Diarrhea 28 (6.7) (17.8) (17.6) 22.1 Nausea 28 (6.7) (16.6) (15.9) 19.6 Upper respiratory tract infection 27 (6.5) (8.4) (16.9) 20.7 Nasopharyngitis 29 (6.9) (7.3) (15.0) 17.8 Tension headache 14 (3.3) (7.3) (9.2) 10.7 Headache 14 (3.3) (5.8) (6.4) 7.1 The apremilast-exposure periods (0 to 52 weeks) included all patients who received apremilast 30 mg BID, regardless of when treatment was initiated. EAIR per 100 patient-years is defined as 100 the number (n) of patients reporting the event divided by patient-years within the phase (up to the first event start date for patients reporting the event).

9 MACE, Potential MACE, Malignancies, and Serious Infections Major cardiac events, potential major cardiac events, malignancies, and serious infections (including opportunistic infections) were balanced between the placebo and apremilast 30 mg BID groups. Period A (Placebo-Controlled Period) Weeks 0 to 16 Apremilast-Exposure Period Weeks 0 to 52 Placebo n=418; Pt-Yrs=116.5 n=1,184; Pt-Yrs=1,127.9 EAIR/100 Pt-Yrs EAIR/100 Pt-Yrs MACE and potential MACE MACE Potential MACE Malignancies Hematologic Skin (excluding melanoma) Solid (including melanoma) Serious infections Non-opportunistic, non-serious infection Non-opportunistic, serious infection Non-systemic, opportunistic infection Systemic, opportunistic infection *The apremilast-exposure period 0 to 52 weeks included all patients who received apremilast 30 mg BID, regardless of when treatment was initiated. EAIR per 100 patient-years is defined as 100 the number (n) of patients reporting the event divided by patient-years (up to the first event start date for patients reporting the event). MACE, major adverse cardiac event.

10 Depression and Suicidality Depression AEs Period A: Placebo, 0.5%, 1.4% Depression as a serious AE, 0.1% (n=1; apremilast exposure 0 to 52 weeks) Suicidality AEs Period A: 1 (0.1%) suicide attempt (apremilast 30 mg BID) and 1 (0.2%) completed suicide (placebo) Based on EAIR per 100 patient-years, no evidence of increasing incidence of depression or suicidality with long-term apremilast exposure

11 Weight Loss and Marked Laboratory Abnormalities At Week 16, mean (median) change from baseline in weight was 1.51 ( 1.00) kg with apremilast 30 mg BID and 0.01 (0.00) kg with placebo. Weight loss >5% was experienced by 13.7% of patients receiving apremilast 30 mg BID and 5.5% receiving placebo. At Week 52, long-term mean (median) change from baseline in weight was 1.99 ( 1.40) kg with apremilast 30 mg BID. Weight loss >5% was experienced by 20.0% of apremilasttreated patients during Weeks 0 to 52. No association between weight loss and diarrhea or nausea/ vomiting has been identified. Weight loss was not associated with any overt medical sequelae or manifestations. Laboratory abnormalities were infrequent and transient among apremilast-treated patients.

12 Conclusions Most AEs were mild or moderate in severity and did not lead to discontinuation. The most frequently reported AEs were nausea, diarrhea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. There was no evidence of increased risk of major cardiac events, malignancies, or serious infections with apremilast treatment. Weight loss is associated with apremilast treatment, without overt clinical complications. Based on EAIR/100 patient-years, there was no evidence of increasing incidence of depression or suicidality with longer apremilast treatment. There were no clinically relevant effects on laboratory measurements. demonstrated an acceptable safety profile and was generally well tolerated for 52 weeks.