Randall Stevens

Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

Objectives Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Conclusions Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT01172938.

Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA). METHODS This phase II, multicenter, randomized, double-blind, placebo-controlled study included the following: a 12-week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12-week treatment-extension phase, with patients in the placebo group re-randomized to receive apremilast; and a 4-week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms. RESULTS Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment-extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re-randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment-extension phase (68.3%) reported ≥ 1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported. CONCLUSION Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.

Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases.

Phosphodiesterase 4 (PDE4) is a key enzyme in the degradation of cyclic adenosine monophosphate and is centrally involved in the cytokine production of inflammatory cells, angiogenesis, and the functional properties of other cell types such as keratinocytes. In this review article, apremilast, a novel small molecule inhibitor of PDE4, is introduced. Apremilast has profound anti-inflammatory properties in animal models of inflammatory disease, as well as human chronic inflammatory diseases such as psoriasis and psoriatic arthritis. Apremilast blocks the synthesis of several pro-inflammatory cytokines and chemokines, such as tumor necrosis factor alpha, interleukin 23, CXCL9, and CXCL10 in multiple cell types. In contrast to the biologics, which neutralize pro-inflammatory mediators at the protein level, apremilast modulates production of these mediators at the level of mRNA expression. Apremilast also interferes with the production of leukotriene B4, inducible nitric oxide synthase, and matrix metalloproteinase and reduces complex inflammatory processes, such as dendritic cell infiltration, epidermal skin thickening, and joint destruction. As this novel PDE4 inhibitor interferes with several key processes of inflammation, it may emerge as a promising new drug for the treatment of chronic inflammatory diseases such as those of the skin and the joints.

Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3)

Objective To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents. Methods Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20 mg twice daily or 30 mg twice daily. The efficacy and safety of apremilast were assessed over 52 weeks. Results At week 16, significantly more patients receiving apremilast 20 mg twice daily (28%) and 30 mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p<0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30 mg twice daily (−0.20) versus placebo (−0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement ≥3%, significantly more apremilast 30 mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection. Conclusions Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52 weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile. Trial registration number NCT01212770.

A Phase III, Randomized, Controlled Trial of Apremilast in Patients with Psoriatic Arthritis: Results of the PALACE 2 Trial

Objective. Apremilast, an oral phosphodiesterase 4 inhibitor, downregulates intracellular inflammatory mediator synthesis by elevating cyclic adenosine monophosphate levels. The PALACE 2 trial evaluated apremilast efficacy and safety in patients with active psoriatic arthritis (PsA) despite prior conventional disease-modifying antirheumatic drugs and/or biologic therapy. Methods. Eligible patients were randomized (1:1:1) to placebo, apremilast 20 mg BID, or apremilast 30 mg BID. At Week 16, patients with swollen and tender joint count improvement < 20% entered early escape, with placebo patients rerandomized (1:1) to apremilast 20 mg BID or 30 mg BID while apremilast patients continued on their initial apremilast dose. At Week 24, patients remaining on placebo were rerandomized to apremilast 20 mg BID or 30 mg BID. The primary endpoint was the proportion of patients achieving > 20% improvement in American College of Rheumatology response criteria (ACR20) at Week 16. Results. In the intent-to-treat population (N = 484), ACR20 at Week 16 was achieved by more patients receiving apremilast 20 mg BID [37.4% (p = 0.0002)] and 30 mg BID [32.1% (p = 0.0060)] versus placebo (18.9%). Clinically meaningful improvements in signs and symptoms of PsA, physical function, and psoriasis were observed with apremilast through Week 52. The most common adverse events were diarrhea, nausea, headache, and upper respiratory tract infection. Diarrhea and nausea generally occurred early and usually resolved spontaneously with continued treatment. Laboratory abnormalities were infrequent and transient. Conclusion. Apremilast demonstrated clinical improvements in PsA for up to 52 weeks, including signs and symptoms, physical function, and psoriasis. No new safety signals were observed. ClinicalTrials.gov identifier: NCT01212757.

Patient-reported Health-related Quality of Life with apremilast for psoriatic arthritis: a phase II, randomized, controlled study.

Objective. Apremilast, a specific inhibitor of phosphodiesterase 4, modulates proinflammatory and antiinflammatory cytokine production. A phase IIb randomized, controlled trial (RCT) evaluated the effect of apremilast on patient-reported outcomes (PRO) in psoriatic arthritis (PsA). Methods. In this 12-week RCT, patients with active disease (duration > 6 mo, ≥ 3 swollen and ≥ 3 tender joints) received apremilast (20 mg BID or 40 mg QD) or placebo. PRO included pain and global assessment of disease activity [visual analog scale (VAS)], Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Medical Outcomes Study Short-Form 36 Health Survey (SF-36) assessing health-related quality of life (HRQOL). Percentages of patients reporting improvements ≥ minimum clinically important differences (MCID) and correlations between SF-36 domains and pain VAS, HAQ-DI, and FACIT-F were determined. Results. Among the 204 randomized patients (52.5% men; mean age 50.6 yrs), baseline SF-36 scores reflected large impairments in HRQOL. Apremilast 20 mg BID resulted in statistically significant and clinically meaningful improvements in physical and mental component summary scores and 7 and 6 SF-36 domains, respectively, compared with no change/deterioration in placebo group. Patients receiving apremilast 20 mg BID and 40 mg QD reported significant improvements ≥ MCID in global VAS scores and FACIT-F versus placebo, and significant improvements in pain VAS scores. Moderate-high, significant correlations were evident between SF-36 domains and other PRO. Conclusion. Apremilast resulted in statistically significant and clinically meaningful improvements in HRQOL, pain and global VAS, and FACIT-F scores.

Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: results from a phase IIb randomized, controlled study

BackgroundApremilast, a specific inhibitor of phosphodiesterase 4, modulates pro-inflammatory and anti-inflammatory cytokine production.ObjectivesApremilast’s effect on patient-reported outcomes (PROs) in patients with moderate to severe psoriasis was evaluated in a phase IIb randomized, controlled trial (NCT00773734).MethodsIn this 16-week, placebo-controlled study, 352 patients with moderate to severe plaque psoriasis received placebo or apremilast (10, 20, or 30 mg BID). PROs included Dermatology Life Quality Index (DLQI), pruritus visual analog scale (VAS), and Short-Form Health Survey (SF-36) to assess health-related quality of life (HRQOL). Changes from baseline and patients reporting improvements ≥minimum clinically important differences (MCID) were analyzed. Correlations between changes across various PRO instruments were explored.ResultsBaseline DLQI (>10 points) and SF-36 MCS and domain scores indicated impairments in HRQOL. At 16 weeks, greater improvements from baseline in DLQI scores were reported with apremilast 20 (−5.9) and 30 mg BID (−4.4) compared with placebo (1.9; P≤0.005 for both), and a greater proportion of patients reported improvements ≥MCID (20 mg BID, 49.4%, 30 mg BID, 44.3%) versus placebo (25.0%; P<0.04). Greater improvements from baseline in pruritus VAS scores were reported with apremilast 20 (−35.5%) and 30 mg BID (−43.7%) versus placebo (−6.1%; P≤0.005). Significant and clinically meaningful improvements in SF-36 mental component summary scores (P≤0.008) and Bodily Pain, Mental Health, and Role-Emotional domains were reported with all apremilast doses (P<0.05), and Social Functioning with 20 and 30 mg BID (P<0.05) and Physical Functioning with 20 mg BID (P<0.03). Correlations between SF-36 scores and DLQI were moderate (r>0.30 and ≤0.60) and low between SF-36 and pruritus VAS (r≤0.30), indicating they measure different aspects of the disease.ConclusionsApremilast treatment resulted in improved HRQOL, including DLQI and pruritus VAS over 16 weeks of treatment, in patients with moderate to severe psoriasis.

SAT0389 Apremilast, an Oral Phosphodiesterase 4 Inhibitor, is Associated with Long-Term (52-Week) Improvements in Enthesitis and Dactylitis in Patients with Psoriatic Arthritis: Results from the Palace 4 Phase 3, Randomized, Controlled Trial

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 4 compared the efficacy/safety of APR with placebo (PBO) in patients (pts) with active PsA who were DMARD-naïve. Objectives Evaluate the impact of APR treatment over 52 wks on enthesitis and dactylitis among PALACE 4 pts. Methods Pts were randomized 1:1:1 to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30). Pts with <20% reduction from BL in SJC or TJC at Wk 16 were required to be re-randomized to APR20 or APR30 if initially randomized to PBO, or continued on the initial APR dose. At Wk 24, all remaining PBO pts were re-randomized to APR20 or APR30. The analysis comprises data from Wks 0-52. Enthesitis was evaluated based on MASES (range 0-13), which indicates the number of painful entheses out of 13 entheses sites. The dactylitis count (range 0-20) is the number of digits (hands and feet) with dactylitis present; each digit is rated as 0 (no dactylitis) or 1 (dactylitis present). Results At Wk 16, a significantly greater proportion of pts receiving APR20 or APR30 achieved the modified ACR20 response vs PBO (primary endpoint). In pts initially randomized to APR and with enthesitis (n=228) and dactylitis (n=173) at BL, APR was associated with improvements in enthesitis and dactylitis over 52 wks, as evidenced by reductions in the MASES and dactylitis count. At Wk 16, median percent changes in MASES were 0.0% (PBO), -20.0% (APR20; P=0.2948), and -50.0% (APR30; P=0.0008). In pts initially randomized to APR and completing 52 wks, median percent changes in MASES were -66.7% (APR20) and -75% (APR30) (Table); 39.6% (APR20) and 45.9% (APR30) of pts achieved a score of 0, indicating no pain at any of the entheses assessed. Median percent changes in dactylitis count at Wk 16 were -50.0% (PBO), -70.8% (APR20; P=0.0691), and -69.2% (APR30; P=0.1494). In pts initially randomized to APR and completing 52 wks, both doses resulted in a median 100% decrease in the dactylitis count; a dactylitis count of 0 was achieved in 68.6% (APR20) and 68.8% (APR30) of pts. The most common AEs reported during the PBO-controlled period were nausea (12.6%), diarrhea (9.4%), and headache (6.0%). The safety profile of APR for up to 52 wks was similar to that observed with APR for up to 24 wks of treatment (PBO-controlled period). Conclusions Among pts continuously treated with APR through 52 wks, sustained improvements in both enthesitis and dactylitis were observed in pts with active PsA, who had enthesitis and dactylitis at BL. APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks. Disclosure of Interest C. Edwards Grant/research support: Celgene Corporation, Pfizer Inc., Roche and Samsung, Consultant for: Celgene Corporation, Pfizer Inc., Roche and Samsung, Speakers bureau: Abbott, Glaxo-Smith Kline, Pfizer Inc., and Roche, A. Wells Grant/research support: Celgene Corporation, A. Adebajo: None declared, A. Kivitz Grant/research support: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc., and UCB, Consultant for: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc., and UCB, Speakers bureau: Pfizer Inc., P. Bird Grant/research support: Celgene Corporation, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, R. Stevens Employee of: Celgene Corporation, J. Aelion Grant/research support: Ardea, AstraZeneca, Bristol-MyersSquibb, CelgeneCorporation, CentocorGalapagos, Genetech, GlaxoSmithKline, HumanGenomeSciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, NovoNordisk, PfizerInc., Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Consultant for: Ardea, AstraZeneca, Bristol-MyersSquibb, CelgeneCorporation, CentocorGalapagos, Genetech, GlaxoSmithKline, HumanGenomeSciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, NovoNordisk, PfizerInc., Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, and UCB DOI 10.1136/annrheumdis-2014-eular.1574

SAT0408 Long-Term Safety and Tolerability of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: Pooled Safety Analysis of Three Phase 3, Randomized, Controlled Trials

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 1, 2, and 3 compared the efficacy and safety of APR with placebo (PBO) in patients with active PsA despite prior conventional DMARDs and/or biologics. Objectives The overall safety and tolerability of APR was assessed in a pooled analysis of PALACE 1, 2, and 3, with APR exposure ≥52 wks. Methods Patients were randomized 1:1:1 to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline (BL) DMARD use (yes/no). Patients with <20% reduction from BL in swollen or tender joint counts were required to be re-randomized to APR20 or APR30 if initially randomized to PBO, or continued on their initial APR dose. At Wk 24, all remaining PBO patients were re-randomized to APR20 or APR30. Patients taking concurrent DMARDs were allowed to continue stable doses (MTX, sulfasalazine, leflunomide, or a combination). Results 1,493 patients received study medication (PBO: 495; APR20: 501; APR30: 497) and were included in the safety population. The APR-exposure period included 720 patients treated with APR20 (766.4 patient-yrs) and 721 with APR30 (769.0 patient-yrs). The nature, incidence, and severity of AEs were comparable through the 24-wk and 52-wk periods (Table). The most common AEs were diarrhea (14.3%), nausea (12.6%), headache (10.1%), URTI (10.3%), and nasopharyngitis (7.4%). Most AEs were mild or moderate in severity. Discontinuations due to AEs (APR20: 7.5%; APR30: 8.3%) were low, occurring primarily in the first 24 wks of treatment. Serious AEs (SAEs) occurred in 6.8% (APR20) and 7.2% (APR30) of patients. One death occurred (APR20) due to multiorgan failure not suspected to be treatment-related. Diarrhea and nausea were predominantly mild and occurred at a reduced incidence after the first month of dosing, with the highest incidence reported in the first 2 wks of treatment. Most cases resolved within 30 days despite continued therapy and without medical intervention. Discontinuation due to GI AEs was 4% through Wk 52, with nausea (1.7%) and diarrhea (1.5%) being the most common. There was 1 case of diarrhea and 1 case of nausea reported as an SAE in the 0 to ≥24-wk period, and no additional cases reported in the 0 to ≥52-wk period. Exposure-adjusted incidence rates of major adverse cardiac events, serious infections including systemic opportunistic infection, or malignancies were comparable to PBO. Laboratory abnormalities were infrequent and transient with no trends or patterns observed. Conclusions APR demonstrated an acceptable safety profile and was generally well tolerated through 52 wks; the nature, incidence, and severity of AEs were comparable through the 24-wk and 52-wk periods. These data do not indicate a need for laboratory monitoring. Disclosure of Interest P. Mease Grant/research support: Celgene Corporation, Novartis, and Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, and UCB, A. Kavanaugh Grant/research support: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc, Roche, and UCB, D. Gladman Grant/research support: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, A. Adebajo: None declared, J. Gomez-Reino Grant/research support: Roche and Schering-Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Schering-Plough, and UCB SA, Speakers bureau: Bristol-Myers Squibb, Roche, Schering-Plough, and Wyeth, J. Wollenhaupt Grant/research support: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB, M. Cutolo Grant/research support: Actelion, Bristol-Myers Squibb, and G. Schett Grant/research support: Abbott, Celgene Corporation, Roche, E. Lespessailles Grant/research support: Amgen, Eli Lilly, Novartis, and Servier, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, R. Stevens Employee of: Celgene Corporation, C. Edwards Grant/research support: Celgene Corporation, Pfizer Inc, Roche, and Samsung, Speakers bureau: Abbott, Glaxo-SmithKline, Pfizer Inc, and Roche, C. Birbara Grant/research support: Amgen, Bristol-Myers Squibb, Incyte, Eli Lilly, Merck, and DOI 10.1136/annrheumdis-2014-eular.5589

Current Status, Goals, and Research Agenda for Outcome Measures Development in Behçet Syndrome: Report from OMERACT 2014.

Objective. There is an unmet need for reliable, validated, and widely accepted outcomes and outcome measures for use in clinical trials in Behçet syndrome (BS). Our report summarizes initial steps taken by the Outcome Measures in Rheumatology (OMERACT) vasculitis working group toward developing a core set of outcome measures for BS according to the OMERACT methodology, including the OMERACT Filter 2.0, and discussions during the first meeting of the BS working group held during OMERACT 12 (2014). Methods. During OMERACT 12, some of the important challenges in developing outcomes for BS were outlined and discussed, and a research agenda was drafted. Results. Among topics discussed were the advantages and disadvantages of a composite measure for BS that evaluates several organs/organ systems; bringing patients and physicians together for discussions about how to assess disease activity; use of organ-specific measures developed for other diseases; and the inclusion of generic, disease-specific, or organ-specific measures. The importance of incorporating patients’ perspectives, concerns, and ideas into outcome measure development was emphasized. Conclusion. The planned research agenda includes conducting a Delphi exercise among physicians from different specialties that are involved in the care of patients with BS and among patients with BS, with the aim of identifying candidate domains and subdomains to be assessed in randomized clinical trials of BS, and candidate items for a composite measure. The ultimate goal of the group is to develop a validated and widely accepted core set of outcomes and outcome measures for use in clinical trials in BS.