Kamal Shah

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate‐to‐severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2)

Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis.

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.

Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2)

Background Randomized, controlled trials demonstrated efficacy and safety of apremilast for moderate‐to‐severe plaque psoriasis and psoriatic arthritis. Objective Assess long‐term safety of oral apremilast in psoriasis patients. Methods Safety findings are reported for 0 to ≥156 weeks from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2. Results The 0 to ≥156–week apremilast‐exposure period included 1184 patients treated twice daily with apremilast 30 mg (1902.2 patient‐years). During 0 to ≤52 weeks, the adverse events (AEs) that occurred in ≥5% of patients included diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. From 0 to ≥156 weeks, no new AEs (affecting ≥5% of the population) were reported. AEs, serious AEs, and study drug discontinuations caused by AEs did not increase with long‐term exposure. During the 0 to ≥156–week period, the rates of major cardiac events (exposure‐adjusted incidence rate [EAIR] 0.5/100 patient‐years), malignancies (EAIR 1.2/100 patient‐years), depression (EAIR 1.8/100 patient‐years), or suicide attempts (EAIR 0.1/100 patient‐years) did not increase in comparison with the rates found during the 0 to ≤52–week period. No serious opportunistic infections, reactivation of tuberculosis, or clinically meaningful effects on laboratory measurements were reported. Limitations This study had a high dropout rate (21% of patients ongoing >156 weeks); most were unrelated to safety concerns. Conclusions Apremilast demonstrated an acceptable safety profile and was generally well tolerated for ≥156 weeks.

Rates of Cardiovascular Disease and Major Adverse Cardiovascular Events in Patients With Psoriatic Arthritis Compared to Patients Without Psoriatic Arthritis.

BackgroundFew studies report estimates of cardiovascular disease (CVD) or major adverse cardiovascular events (MACE) in patients with psoriatic arthritis (PsA). ObjectiveTo estimate rates of incident CVD and MACE in patients with PsA compared to patients without PsA. MethodsUsing the Clinical Practice Research Datalink, we conducted 2 cohort studies of patients with PsA compared to patients without PsA or psoriasis matched on age, sex, general practice, and calendar time: 1 study of CVD and 1 study of MACE. In each study, we excluded patients who had a study outcome before cohort entry. Cases were patients with a first-time diagnosis of CVD or MACE recorded during follow-up. We estimated incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals (95% CI) and stratified results in the PsA cohort by exposure to systemic PsA treatments. ResultsThe IR of CVD was higher in the patients with PsA compared to those without PsA (12.8/1000 person-years [PYs] [95% CI, 11.9–13.7] and 9.6/1000 PYs [95% CI, 9.3–9.0]; IRR, 1.33 [95% CI, 1.23–1.44]). The IR of MACE was slightly higher in the PsA compared to the non-PsA cohort (4.6/1000 PYs [95% CI, 4.1–5.1] and 3.5/1000 PYs [95% CI, 3.4–3.7]; IRR, 1.30 [95% CI, 1.15–1.47]). Among the patients with PsA, IRs were higher for those who received PsA treatments for both outcomes but did not differ significantly by type of treatment received. ConclusionsThe rates of CVD and MACE were slightly higher in the patients with PsA compared to the patients without PsA. Among the patients with PsA, rates of both outcomes were higher among those who received prescriptions for systemic PsA treatments.

THU0432 Long-Term (104-Week) Safety Profile 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), a phosphodiesterase 4 inhibitor, helps regulate the immune responses in psoriatic arthritis (PsA). PALACE 1-3 compared APR efficacy/safety with placebo (PBO) in patients (pts) with active PsA despite prior conventional DMARDs and/or biologics. Objectives Overall APR safety/tolerability was assessed in a pooled analysis of PALACE 1-3, with APR exposure ≤104 wks. Methods Pts were randomized (1:1:1) to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). The PBO-controlled phase continued to Wk 24, with an early escape option at Wk 16. Double-blind APR treatment continued to Wk 52; pts could continue to receive APR during an open-label, long-term treatment phase. We report safety findings from the APR-exposure period (Wks 0 to ≤104). Results 1493 pts were randomized and received ≥1 dose of study medication (PBO: n=495; APR20: n=501; APR30: n=497). A total of 1441 (1209.3 pt-yrs) and 1028 (907.7 pt-yrs) pts received APR in the Wk 0 to ≤52 and Wk >52 to ≤104 periods, respectively. During Wks 0 to ≤52, AEs occurring in ≥5% of APR-exposed pts were diarrhea, nausea, headache, URTI, and nasopharyngitis (Table). Most AEs were mild/moderate in severity during the Wk 0 to ≤104 APR-exposure period; in general, no increase was seen in the incidence/severity of AEs with longer term exposure. During Wks >52 to ≤104, diarrhea (2.9%), nausea (1.8%), and headache (3.0%) occurred at lower rates vs Wks 0 to ≤52 (Table). In Wks 0 to ≤52, 87 pts reported serious AEs (SAEs) vs 71 pts in Wks >52 to ≤104. In few system organ classes, there were numerically more pts reporting SAEs but it did not indicate any specific organ involvement. The vast majority of the SAEs were reported by 1 pt each. There was no increase in cardiac, malignant neoplasm, opportunistic infection, or psychiatric disorder related SAEs and no cases of tuberculosis (new/reactivation) reported with either APR dose. Discontinuations due to AEs occurred at a lower rate (2.3%) during Wks >52 to ≤104. Marked laboratory abnormalities were generally infrequent and most returned to baseline with continued treatment or were associated with a concurrent medical condition. Conclusions APR demonstrated an acceptable safety profile and was generally well tolerated for up to 104 wks, with no new safety concerns identified with long-term exposure. These data continue to support the lack of a need for specific laboratory monitoring with APR. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Speakers bureau: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, and UCB, A. Adebajo: None declared, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, J. Gomez-Reino Grant/research support from: 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, S. Hall Consultant for: Boehringer Ingelheim, MSD, Roche Schering Plough, Servier, and Wyeth., Paid instructor for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GlaxoSmithKline, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, and Wyeth, Speakers bureau: Boehringer Ingelheim, GlaxoSmithKline, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, and Wyeth;, A. Kavanaugh Grant/research support from: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc, Roche, and UCB, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, and Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, and Servier, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, and UCB, Consultant for: Abbott, Celgene Corporation, Roche, and UCB, K. Shah Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB, Consultant for: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB

Incidence rates of suicidal behaviors and treated depression in patients with and without psoriatic arthritis using the Clinical Practice Research Datalink

Abstract Objective: To estimate rates of suicidal behaviors and treated depression in patients with psoriatic arthritis (PsA) in comparison to non-PsA patients. Methods: Using the Clinical Practice Research Datalink, we conducted a cohort study of patients with PsA compared to non-PsA patients. Patients with codes for suicidal behaviors (ideation, attempts, and suicide) and treated depression (diagnosis plus anti-depressant prescription) recorded during follow-up were identified as cases. We estimated incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for each outcome and stratified results in the PsA cohort by receipt of systemic PsA drugs. Results: The rates of suicide ideation, attempt, and suicide were similar for PsA and non-PsA patients [IRR = 0.99 (95%CI: 0.67–1.47), IRR = 1.07 (95%CI: 0.86–1.34), and 0.34 (95%CI: 0.05–2.48), respectively] and rates of suicidal behaviors were slightly higher among PsA patients who received PsA drugs compared to those who did not. PsA patients had slightly higher rate of treated depression compared to non-PsA patients [IRR = 1.38 (95%CI: 1.27–1.49)] and were significantly higher in PsA patients who received drugs [IRR = 1.59 (95%CI: 1.35–1.86)]. Conclusions: Rate of depression was higher in patients with PsA compared to non-PsA patients. The rate of suicidal behaviors was similar between the two cohorts.

Rates of Cancers and Opportunistic Infections in Patients With Psoriatic Arthritis Compared With Patients Without Psoriatic Arthritis.

ObjectivesThis study aimed to estimate rates of cancer or opportunistic infection in patients with psoriatic arthritis (PsA) compared with patients without PsA. MethodsUsing the Clinical Practice Research Datalink, we conducted a cohort study of patients with a PsA diagnosis and patients without such diagnosis, matched on age, sex, general practice, and calendar time, to assess the incidence of cancers (solid, hematologic, and nonmelanoma skin cancer) and opportunistic infections. We estimated incidence rates (IRs) and IR ratios (IRRs) with 95% confidence intervals (CIs) for each outcome and stratified results in the PsA cohort by receipt of systemic PsA drugs. ResultsThe rate of hematologic cancer was slightly higher in the PsA cohort compared with the non-PsA cohort (IRR, 1.52; 95% CI, 1.10–2.10), whereas the rates of solid cancer and of nonmelanoma skin cancer were similar between the PsA and non-PsA cohorts (IRR, 1.01; 95% CI, 0.90–1.13; and IRR, 0.97; 95% CI, 0.82–1.14, respectively). Incidence rates were higher for PsA patients who received prescriptions for PsA drugs compared with those who did not. The IRs for infection were higher in the PsA compared with the non-PsA cohort (IRR, 1.39; 95% CI, 1.31–1.47) and were significantly higher in patients who received prescriptions (IRR, 1.71; 95% CI, 1.52–1.91). ConclusionsThe rates of solid and nonmelanoma skin cancers were similar in patients with PsA compared with patients without PsA, but the rates of hematologic cancer and opportunistic infections were higher in patients with PsA. In patients with PsA, rates of all outcomes were higher among those who received prescriptions for systemic PsA therapy.

THU0435 DAS-28 Remission and Improvements in Skin Disease over 3 Years of Treatment with Apremilast: Results from The Palace 3 Study in Dmard/biologic-Experienced Active PsA Patients

Background Treatment goals for active psoriatic arthritis (PsA) include long-term control of both skin and joint symptoms. Achievement of remission in 28-joint count Disease Activity Score (DAS-28) using C-reactive protein (CRP), clinically important changes in DAS-28 (CRP), reduction in swollen joint count (SJC), or decrease in skin disease may be used as goals of treatment.1 PALACE 3 (NCT01212770) included PsA patients with active joint disease with an active skin lesion at the time of enrollment. Objectives Assess long-term treatment responses across PsA manifestations in patients treated with apremilast (APR) for 3 years. Methods Patients were stratified by baseline DMARD use (yes/no) and psoriasis involvement of the body surface area (<3%/≥3%) and randomized (1:1:1) to placebo (PBO), APR 30 mg BID (APR30), or APR 20 mg BID (APR20). After a PBO-controlled phase of 24 wks, all patients were treated with APR30 or APR20 and could enroll in long-term follow-up. Efficacy assessments in years 2 and 3 were conducted at Wks 65, 78, 91, 104, 117, 130, 143, and 156. Results 505 patients were randomized and received ≥1 dose of study medication (PBO: n=169; APR30: n=167; APR20: n=169). A total of 89% (249/281) of patients starting the third year of APR therapy completed the Wk 156 visit. Patients treated with APR30 demonstrated sustained decreases in disease activity at Wk 156, as shown by mean decreases in DAS-28 (CRP) of −1.58; 79.1% achieved a good/moderate EULAR response and 41.0% achieved DAS-28 (CRP) remission. Sustained relief across PsA manifestations, including SJC, a marker of inflammation, was also demonstrated (Table); at Wk 156, APR30 resulted in a mean 78.3% decrease in SJC, 65.5% of patients had a swollen joint count of 0 or 1. Decreases in disability and maintenance of functionality were demonstrated by sustained decreases in HAQ-DI scores (Table). Continued effect on skin disease was shown by decreases in skin involvement, as measured by the PASI; 54.7% of APR30 patients had a baseline PASI >5 and 27.3% had a baseline PASI >10; at 156 wks, 64.7% had a PASI <3, and 83.8% had a PASI of ≤5. PASI-75 and PASI-50 also signified clinically significant relief (Table). No new safety concerns were identified after 156 wks of APR treatment. During Wks >104 to ≤156 of APR exposure, adverse events (AEs) occurring in ≥5% of patients were nasopharyngitis and urinary tract infection; most AEs were mild or moderate in severity. Serious AEs occurred in 7.8% of APR patients during Wks >104 to ≤156, similar to rates seen for the earlier study periods; few discontinuations due to AEs (2.1%) occurred over Wks >104 to ≤156. Conclusions Over 156 wks, among patients continuing in the study, APR demonstrated sustained and clinically important improvements in PsA signs/symptoms, including physical function and associated psoriasis. APR was generally well tolerated and continued to demonstrate an acceptable safety profile with long-term use. References Gossec et al. Ann Rheum Dis. 2015 Dec 7. doi: 10.1136/annrheumdis-2015-208337. [Epub ahead of print]. Disclosure of Interest C. Edwards Grant/research support from: Celgene Corporation, Pfizer Inc, Roche, Samsung, Consultant for: Celgene Corporation, Pfizer Inc, Roche, Samsung, Speakers bureau: Abbott, Glaxo-SmithKline, Pfizer Inc, Roche, F. Blanco Grant/research support from: Celgene Corporation, J. Crowley Grant/research support from: AbbVie, Amgen, Celgene, Janssen, Merck, and Pfizer, Consultant for: AbbVie, Amgen, Speakers bureau: AbbVie, M. McIlraith Employee of: Celgene Corporation, K. Shah Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, C. Birbara Grant/research support from: Amgen, Bristol-Myers Squibb, Incyte, Eli Lilly, Merck, Pfizer Inc