Abstract Background: Methods: Results: Conclusion:

Transcription

1 1055 Two-Year Safety of, an Oral Phosphodiesterase 4 Inhibitor, in Patients With Moderate to Severe Psoriasis: Results From a Phase 3, Randomized, Controlled Trial () Kim A. Papp, MD 1 ; Kristian Reich, MD 2 ; Jeffrey M. Sobell, MD 3 ; Alan Menter, MD 4 ; Jean-Philippe Lacour, MD 5 ; Sergio Chimenti, MD 6 ; ChiaChi Hu, EdM, MS 7 ; Robert M. Day, PhD 7 ; Kamal Shah, MD 7 ; Christopher E.M. Griffiths, MD 8 1 Probity Medical Research, Waterloo, ON, Canada; 2 SCIderm Research Institute and Dermatologikum Hamburg, Hamburg, Germany; 3 Tufts University School of Medicine, Chestnut Hill, MA; 4 Baylor University Medical Center, Dallas, TX; 5 Department of Dermatology, Hôpital Archet-2, CHU de Nice, Nice, France; 6 University of Rome Tor Vergata, Rome, Italy; 7 Celgene Corporation, Warren, NJ; 8 The Dermatology Centre; The University of Manchester, Manchester, UK Presented at: the 73rd Annual Meeting of the American Academy of Dermatology; March 20-24, 2015; San Francisco, CA. This study was sponsored by Celgene Corporation.

2 Disclosures Dr. Kim A. Papp has received honoraria and research grants as a consultant, an investigator, a speaker, an advisory board member, or scientific officer for Abbott, AbbVie, Amgen, Astellas, Basilea, Biogen-Idec, Celgene, Centocor/Janssen Biotech, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, LEO Pharma, MSD, Merck-Serono, Novartis, Pfizer, UCB, and Wyeth/Pfizer. Dr. Kristian Reich has received honoraria as a consultant and/or advisory board member and/or acted as a paid speaker and/or participated in clinical trials sponsored by Abbott, AbbVie, Amgen, Basilea, Biogen-Idec, Celgene, Centocor, Eli Lilly, Forward Pharma, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Medac, MSD (Essex Pharma, Schering-Plough), Novartis, Ocean Pharma, Pfizer (Wyeth), and UCB. Dr. Jeffrey M. Sobell has received honoraria as a consultant, and/or advisory board member, and/or acted as a paid speaker, and/or participated in clinical trials sponsored by AbbVie, Amgen, Celgene, Eli Lilly, Janssen Biotech, Merck, and Novartis. Dr. Alan Menter has been an investigator and consultant for AbbVie, Allergan, Amgen, Convoy Therapeutics, Eli Lilly, Janssen Biotech, LEO Pharma, Novartis, Pfizer, Syntrix, and Wyeth; served on the advisory board for AbbVie, Allergan, Amgen, Boehringer Ingelheim, Genentech, Janssen Biotech, LEO Pharma, and Pfizer; has been a speaker for AbbVie, Amgen, Janssen Biotech, LEO Pharma, and Wyeth; has been an investigator for ApoPharma, Celgene, Merck, and Symbio; and has been a consultant for XenoPort Dr. Jean-Philippe Lacour has received honoraria as a consultant and/or advisory board member and/or acted as a paid speaker and/or participated in clinical trials sponsored by AbbVie, Amgen, Celgene, Eli Lilly, Forward Pharma, GlaxoSmithKline, LEO Pharma, Medac, Novartis, and Pfizer. Dr. Sergio Chimenti has received honoraria and research grants as an investigator and/or advisory board member for Abbott, Celgene, Janssen, and Pfizer. Dr. Kamal Shah, Ms. ChiaChi Hu, and Dr. Robert M. Day are employees of Celgene Corporation. Dr. Christopher E.M. Griffiths has received honoraria and research grants as a consultant, investigator, and/or speaker AbbVie, Actelion, Celgene, Eli Lilly, GSK-Stiefel, Janssen, LEO Pharma, MSD, Novartis, Pfizer, Sandoz, and UCB.

3 Abstract Background:, a phase 3, randomized trial with an open-label extension, evaluated the efficacy/safety of apremilast (APR) in patients (pts) with moderate to severe plaque psoriasis. Methods: Safety findings are reported from the APR-exposure periods, Wks 0-52 and > Results: 844 pts (624.4 pt-yrs) were randomized; 444 (350.7 pt-yrs) continued in the second year. AEs occurring in 5% of pts were diarrhea (18.7%), nausea (15.2%), upper respiratory tract infection (18.2%), nasopharyngitis (13.7%), tension headache (9.6%), and headache (6.5%) during Wks 0-52; and upper respiratory tract infection (9.7%) and nasopharyngitis (6.8%) during Wks > For either period, most AEs were mild or moderate in severity; severe AEs occurred in 6.2% and 3.2% of pts during Wks 0-52 and >52-104, respectively. Diarrhea/nausea rates were lower during Wks > (1.8% and 0.7%, respectively) than Wks 0-52 (18.7% and 15.2%). In APR-treated pts reporting diarrhea and nausea, more than half occurred within 2 wks following the first dose, were predominantly mild in severity, and generally resolved within 4 wks. Discontinuation rates due to AEs were low (7.8% and 2.9% in Wks 0-52 and >52-104, respectively). Depression was reported in 2.0% and 0.5% of pts during Wks 0-52 and >52-104, respectively. No APR-treated pt reported suicidal ideation, suicide attempt, or completed suicide up to 104 wks. Serious AEs occurred in 4.5% and 5.4% of pts during Wks 0-52 and >52-104, respectively. No serious diarrhea was reported during Wks > There was 1 case each of serious depression during Wks 0-52 and Wks > Only 6 (1.4%) serious infections were reported during Wks >52-104; none were opportunistic infections. No cases of reactivation of tuberculosis were reported with APR. Of pts with evaluable data (n=473; mean baseline weight, kg), mean/median percent change from baseline was -2.07%/-1.59% at Wk 52. At Wk 104 (n=202), mean/median percent change from baseline was -1.94%/ -1.56%. One death was reported (Wks >52-104): 69 y/o male pt (history of DM, HTN, and hyperlipidemia) had a fatal CVA (Day 666 on APR). One death has been previously reported (Wks 0-52). There were no clinically meaningful changes on laboratory measurements. Conclusion: APR demonstrated an acceptable safety and tolerability profile for up to 104 wks, with no new safety signals identified.

4 Introduction and Objective Psoriasis is a chronic, systemic inflammatory disease affecting 1% to 3% of the world s population. 1-3 Currently available therapies are often compromised by adverse events (AEs), safety and tolerability issues, and route of administration (injection/infusion vs. oral). 4, an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. 5 was approved by the US Food and Drug Administration in 2014 and by the European Commission in 2015 for the treatment of psoriasis and psoriatic arthritis. 6,7 ESTEEM is a phase 3 clinical trial program comprising 2 randomized, placebocontrolled studies evaluating the efficacy, safety, and tolerability of apremilast for the treatment of moderate to severe plaque psoriasis. This presentation describes the long-term (2-year) safety of apremilast in patients with moderate to severe plaque psoriasis in. 1. 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, September Otezla (apremilast) summary of product characteristics. Uxbridge, UK: Celgene Europe Ltd.; January ESTEEM=Efficacy and Safety Trial Evaluating the Effects of in Psoriasis.

5 : Study Design Adult patients aged 18 years and older with moderate to severe plaque psoriasis Period A Period B Period C Week 0 Week 16 Week 32 Week 52 * PASI-75 At time of loss of effect (loss of PASI-75) SCREEN RANDOMIZE (1:2) < PASI-75 PASI-75 * ± topicals, UVB < PASI-75 ± 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 re-started apremilast at the time of loss of effect vs. baseline (loss of PASI-75) but no later than Week 52. Patients initially on placebo or randomized to apremilast who did not attain a PASI-75 were able to add topicals and/or UVB at Week 32 at the discretion of the investigator. PASI-75=a 75% reduction from baseline Psoriasis Area and Severity Index score.

6 Baseline Patient Demographics and Disease Characteristics N=844, Full Analysis Set n=282 n=562 Age, mean, years Male, n (%) 194 (68.8) 379 (67.4) BMI, mean, kg/m Duration of plaque psoriasis, mean, years PASI score (0-72), mean PASI >20, n (%) 87 (30.9) 158 (28.1) Body surface area, mean, % Body surface area >20%, n (%) 149 (52.8) 266 (47.3) spga = 4 (severe), n (%) 89 (31.6) 161 (28.6) Pruritus VAS score (0-100 mm), mean DLQI score (0-30), mean ScPGA score 3, n (%) 189 (67.0) 374 (66.5) NAPSI score for target nail, mean* Prior systemic therapy (conventional +/or biologic), n (%) 150 (53.2) 301 (53.6) Prior conventional systemic therapy, n (%) 102 (36.2) 212 (37.7) Prior biologic therapy, n (%) 80 (28.4) 162 (28.8) The n reflects the number of patients who were randomized; actual number of patients available for each end point may vary. *n=195 (placebo) and n=366 (apremilast ). BMI=body mass index; DLQI=Dermatology Life Quality Index; NAPSI=Nail Psoriasis Severity Index; ScPGA=Scalp Physician Global Assessment; VAS=visual analog scale.

7 Overview of Adverse Events Period A (-Controlled) 0 to 16 Weeks -Exposure Period 0 to 52 Weeks -Exposure Period >52 to 104 Weeks Patients, n (%) n=282 n=560 n=804 n=444 1 AE 157 (55.7) (69.3) (79.4) (57.9) severe AE 9 (3.2) (3.6) (6.2) (3.2) serious AE 8 (2.8) (2.1) (4.5) (5.4) 7.0 AE leading to drug withdrawal 9 (3.2) (5.2) (7.8) (2.9) 3.7 Most AEs were mild or moderate in severity and did not lead to discontinuation. The incidence of serious AEs was low. The EAIR for serious AEs did not increase with longer apremilast exposure, compared with the placebo-controlled period. Two deaths occurred with apremilast exposure (n=1, 0 to 52 weeks; n=1, >52 to 104 weeks) 30-year-old woman; history of depression and obesity; fatal cardiac failure on Day year-old man; history of diabetes, hypertension, and hyperlipidemia; fatal cerebrovascular accident on Day 666 of apremilast exposure The apremilast-exposure periods (0 to 52 weeks and >52 to 104 weeks) included all patients who received apremilast, regardless of when treatment was initiated. Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times 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).

8 Adverse Events 5% in Any Treatment Group Period A (-Controlled) 0 to 16 Weeks -Exposure Period 0 to 52 Weeks -Exposure Period >52 to 104 Weeks Patients, n (%) n=282 n=560 n=804 n=444 Diarrhea 20 (7.1) (18.8) (18.7) (1.8) 2.3 URTI 21 (7.4) (10.2) (18.2) (9.7) 13.1 Nausea 19 (6.7) (15.7) (15.2) (0.7) 0.9 Nasopharyngitis 23 (8.2) (7.3) (13.7) (6.8) 8.9 Tension headache 12 (4.3) (7.3) (9.6) (1.6) 2.0 Headache 13 (4.6) (5.5) (6.5) (0.7) 0.9 Most frequently reported AEs during Period A (placebo-controlled) and the apremilast-exposure periods were diarrhea, URTI, nausea, nasopharyngitis, tension headache, and headache. Depression was reported in 0 (0.0%) placebo-treated patients during 0 to 16 weeks and 16 (2.0%) and 2 (0.5%) apremilast-treated patients during 0 to 52 weeks and >52 to 104 weeks, respectively. The apremilast-exposure periods (0 to 52 weeks and >52 to 104 weeks) included all patients who received apremilast, regardless of when treatment was initiated. Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times 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). URTI=upper respiratory tract infection.

9 Serious Adverse Events ( 2 Patients in Any Treatment Group) Period A (-Controlled) 0 to 16 Weeks -Exposure Period 0 to 52 Weeks -Exposure Period >52 to 104 Weeks Patients, n (%) n=282 n=560 n=804 n=444 Urinary tract infection (0.2) Coronary artery disease (0.4) Acute MI (0.2) COPD (0.2) Osteoarthritis (0.1) (0.5) 0.6 Nephrolithiasis (0.4) The incidence of serious AEs was not driven by any single preferred term or specific, individual organ toxicity. Depression was reported as a serious AE in 1 patient exposed to apremilast during each period (0.1%, 0 to 52 weeks; 0.2%, >52 to 104 weeks). Suicidal ideation, suicide attempt, or completed suicide was not reported in any apremilast-treated patient up to 104 weeks. The apremilast-exposure periods (0 to 52 weeks and >52 to 104 weeks) included all patients who received apremilast, regardless of when treatment was initiated. Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times 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). COPD=chronic obstructive pulmonary disease; MI=myocardial infarction.

10 Adverse Events Leading to Discontinuation (>2 Patients in Any Treatment Group) Period A (-Controlled) 0 to 16 Weeks -Exposure Period 0 to 52 Weeks -Exposure Period >52 to 104 Weeks Patients, n (%) n=282 n=560 n=804 n=444 Nausea 1 (0.4) (1.8) (1.7) Diarrhea 1 (0.4) (1.3) (1.2) Psoriasis 1 (0.4) (0.4) (0.9) (0.9) 1.1 Vomiting (0.5) Headache (0.5) (0.4) Tension headache (0.4) (0.4) Dyspepsia (0.5) (0.4) Psoriatic arthropathy (0.2) (0.7) 0.9 Nausea and diarrhea most commonly led to discontinuation during 0 to 52 weeks; few patients discontinued apremilast due to an AE during >52 to 104 weeks. The apremilast-exposure periods (0 to 52 weeks and >52 to 104 weeks) included all patients who received apremilast, regardless of when treatment was initiated. Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times 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).

11 Major Cardiac Events, Potential Major Cardiac Events, Malignancies, and Infections Period A (-Controlled) 0 to 16 Weeks -Exposure Period 0 to 52 Weeks -Exposure Period >52 to 104 Weeks Patients, n (%) n=282 n=560 n=804 n=444 Major cardiac events* 1 (0.4) 2 (0.4) 4 (0.5) 3 (0.7) Potential major cardiac events 2 (0.2) Malignancies Hematologic Skin Basal cell carcinoma Squamous cell carcinoma (skin) Keratoacanthoma Solid tumors Anal cancer Breast cancer Renal cell carcinoma 1 (0.4) 1 (0.4) 13 (1.6) 6 (0.7) 4 (0.5) 3 (0.4) 2 (0.2) 1 (0.1) 1 (0.1) 2 (0.5) Serious infections Urinary tract infection Diverticulitis Pneumonia Appendicitis Bacterial infection Brain abscess Nasopharyngitis Sepsis Viral meningitis 1 (0.4) 1 (0.4) 2 (0.2) 1 (0.1) 1 (0.1) Serious opportunistic infection Major cardiac events, solid malignancies, hematologic tumors, and serious infections did not increase with long-term exposure to apremilast. *Cardiac failure (death), cerebrovascular accident (death), (acute) myocardial infarction, and hemorrhagic stroke. Unstable angina, transient ischemic attack. No melanomas were reported. Brain abscess secondary to otitis media; for reported sepsis, no organism was identified in blood and no intravenous antibiotic treatment was initiated.

12 Select Marked Laboratory Abnormalities Changes in laboratory parameters were transient and generally resolved with continued treatment; no trend was observed across organ systems. Period A (-Controlled) 0 to 16 Weeks -Exposure Period 0 to 52 Weeks -Exposure Period >52 to 104 Weeks Patients, n/m (%) ALT >3 ULN, U/L 1/274 (0.4) 1/555 (0.2) 4/798 (0.5) 2/434 (0.5) AST >3 ULN, U/L 1/274 (0.4) 2/554 (0.4) 7/797 (0.9) 4/434 (0.9) Total bilirubin >1.8 ULN, μmol/l 1/274 (0.4) 1/555 (0.2) 4/798 (0.5) 0/434 (0.0) Hemoglobin A1C >9% 1/258 (0.4) 1/527 (0.2) 1/773 (0.1) 3/433 (0.7) Total cholesterol >7.8 mmol/l 6/256 (2.3) 2/528 (0.4) 14/774 (1.8) 9/433 (2.1) Lymphocytes < /L 7/274 (2.6) 7/553 (1.3) 22/796 (2.8) 3/434 (0.7) Neutrophils < /L 0/274 (0.0) 0/553 (0.0) 1/796 (0.1) 2/434 (0.5) Note: All values are non-fasting. The apremilast-exposure periods (0 to 52 weeks and >52 to 104 weeks) included all patients who received apremilast, regardless of when treatment was initiated. n/m=number of patients with 1 occurrence of the abnormality at any time point/number of patients with 1 post-baseline value. ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.

13 Body Weight Assessments -Exposure Period 0 to 16 Weeks n=560 -Exposure Period 0 to 52 Weeks n=804 -Exposure Period >52 to 104 Weeks n=444 Patients with evaluable data, n* Baseline weight, kg, mean (SD) 93.5 (21.6) 93.5 (22.4) 93.0 (21.1) Mean (SD) % change from baseline (3.8) (5.6) (7.2) Median (min, max) % change from baseline (-22.6, 18.8) (-25.7, 17.2) (-26.3, 33.7) Patients with >5% weight loss, n/m (%) 71/531 (13.4) 144/777 (18.5) 109/435 (25.1) Weight decrease was reported as an AE in 1.0% (8/804) of patients during 0 to 52 weeks and in 0.5% (2/444) during >52 to 104 weeks; none were serious AEs. The majority of patients receiving apremilast maintained their body weight within ±5% of baseline, regardless of duration of exposure (76.1%, 0 to 52 weeks; 65.1%, >52 to 104 weeks). From >52 to 104 weeks, there was no increase in the number of patients with weight loss >5%. *Patients with a baseline value and a post-baseline value at the time point. m=number of patients with a baseline value and at least 1 post-baseline value; percentages are based on m. The apremilast-exposure periods (0 to 52 weeks and >52 to 104 weeks) included all patients who received apremilast, regardless of when treatment was initiated.

14 Conclusions demonstrated an acceptable safety profile and was generally well tolerated for up to 104 weeks of exposure. Most AEs were mild or moderate in severity and did not lead to discontinuation. Incidence rates of major cardiac events, solid tumors, hematological malignancies, and serious infections were comparable between the placebo and apremilast arms in Period A. No increase in incidence rates was noted with longer term exposure to apremilast (between weeks). The majority of patients receiving apremilast maintained their body weight within ±5% of baseline, regardless of duration of exposure. There was no increase in the number of patients with significant weight loss with longer term apremilast exposure. No new safety signals for apremilast were identified in the second year of exposure as compared with the first.