J. Gomez-Reino

Safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the monoclonal antibody ASK8007 blocking osteopontin in patients with rheumatoid arthritis: a randomised, placebo controlled, proof-of-concept study

Objectives Osteopontin is an extracellular matrix protein with diverse immunomodulatory functions. The authors assessed the safety, tolerability, pharmacokinetics, pharmacodynamics and initial efficacy of the humanised monoclonal antibody ASK8007, which blocks osteopontin. Methods In this double-blind, multicentre, combined first-in-man, single-dose escalation (phase I, part A) and proof-of-concept, multiple-dose (phase IIA, part B) study, rheumatoid arthritis (RA) patients with active disease were randomly assigned to receive ASK8007 or placebo intravenously. Safety monitoring, pharmacokinetic and pharmacodynamic analyses and clinical assessments were performed throughout the study. The expression of phenotypic cell markers was evaluated in synovial tissue biopsy samples obtained at baseline and 43 days after initiation of treatment (part B) by immunohistochemistry and digital image analysis. Two co-primary efficacy endpoints were the change from baseline in the disease activity score evaluated in 28 joints (DAS28) and the change from baseline in the number of CD68 synovial sublining macrophages, both assessed on day 43 (part B). Results ASK8007 was overall safe and well tolerated up to the highest studied dose (20 mg/kg). Quantifiable concentrations of ASK8007 were detected in synovial fluid. No differences were observed for changes from baseline in DAS28 and CD68 sublining macrophages between ASK8007 and placebo-treated patients. Within the ASK8007 treatment group, there were also no apparent clinical responses or changes in sublining macrophages. In addition, ASK8007 treatment did not change other assessed biomarkers. Conclusions Osteopontin blockade is well tolerated and not related to safety concerns. These results consistently show that osteopontin blockade is unlikely to induce robust clinical improvement in RA patients.

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

SAT0436 Durability of apremilast response in patients with psoriatic arthritis: long-term (208-week) results from the palace 1 trial

Background Optimizing treatment choice in psoriatic arthritis (PsA) necessitates an understanding of the long-term effects of therapies across varied manifestations of this complex disease. Data from 4 years of apremilast (APR) treatment in PALACE 1 were used to examine disease control across markers of active inflammation, such as SJC, as well as improvements in patient (pt) functionality, as assessed using the HAQ-DI. Objectives Evaluate long-term outcomes with APR treatment after ≥1 DMARD or biologic in pts with active PsA. Methods Pts were randomized (1:1:1) to placebo (PBO), APR 30 mg BID (APR30), or APR 20 mg BID (APR20). The PBO-controlled phase continued to Wk 24, at which time all remaining PBO pts were re-randomized to APR30 or APR20. Double-blind APR treatment continued to Wk 52; pts could continue APR for up to 4 additional years in an open-label extension. Results 504 pts were randomized and received ≥1 dose of study medication (PBO: n=168; APR30: n=168; APR20: n=168); 86.9% (225/259) of pts entering the third year completed 208 wks of APR treatment; overall, this is 44.6% (225/504) of pts randomized at baseline (BL). At Wk 52, 53.2% of APR30 pts achieved a modified ACR20 response (Table), regardless of when APR was started (BL, Wk 16, or Wk 24). At Wk 208, a sustained response rate was observed in APR30 pts, as shown by an ACR20 response rate of 67.5%. Marked improvements in SJC were seen throughout the study, with a mean percent decrease of −84.2% at Wk 208; TJC reductions were consistent (Table). Functionality is of paramount importance to pts; large improvements were seen in HAQ-DI score, with a mean change of −0.47. Pts also note fatigue as a disease- or treatment-related impairment; a mean improvement of 5.7 was seen in FACIT-F score at Wk 208 (Table), and the pt population reached a mean score of 35.7. In addition, long-term treatment led to the maintenance of the proportions meeting the minimal clinically important difference in HAQ-DI score change, achieving ACR50/ACR70 responses and reaching PASI-75 and PASI-50 responses (Table). No new safety concerns were identified with APR treatment up to 208 wks. During Wks >156 to ≤208, the only adverse event (AE) occurring in ≥5% of APR30-exposed pts was URTI (5.2%); most AEs were mild/moderate in severity. Among APR30-exposed pts, serious AEs occurred in 6.7% of pts in Wks >156 to ≤208, consistent with earlier data. Importantly, few discontinuations due to AEs occurred throughout the long-term treatment period. Conclusions APR30 demonstrated sustained, clinically meaningful improvements in signs and symptoms of PsA, physical function, and associated psoriasis over 208 wks. APR30 continued to demonstrate a favorable safety profile and was generally well tolerated. Disclosure of Interest A. Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB, Consultant for: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB, J. Gomez-Reino Grant/research support from: Roche and Schering-Plough, Consultant for: BMS, Pfizer, Roche, Schering-Plough, UCB, S. Hall Consultant for: Boehringer Ingelheim, MSD, Roche, Schering-Plough, Servier, Wyeth, Paid instructor for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GSK, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, Wyeth, Speakers bureau: Boehringer Ingelheim, GSK, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, Wyeth, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, Servier, P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Genentech, Janssen, Eli Lilly, Pfizer, UCB, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, UCB, Consultant for: Abbott, Celgene Corporation, Roche, UCB, M. McIlraith Employee of: Celgene Corporation, N. Delev Employee of: Celgene Corporation, M. Paris Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, BMS, MSD, Pfizer, UCB, Consultant for: Abbott, BMS, MSD, Pfizer, UCB

AB0785 Consistent safety profile with up to 4 years of apremilast treatment: analysis of data from 1493 patients with psoriatic arthritis in 3 large, phase iii, long-term studies

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, regulates immune activity in psoriatic arthritis (PsA) patients. Safety data were pooled from the phase 3 PALACE 1, 2, and 3 studies. Objectives Evaluate the long-term safety of APR treatment for up to 4 years in patients with active PsA despite prior conventional DMARDs and/or biologics. Methods Patients were randomized at baseline (1:1:1) to placebo (PBO), APR 30 mg BID (APR30), or APR 20 mg BID (APR20). PBO patients were re-randomized to APR30 or APR20 at Week 16 (early escape) or Week 24. Double-blind APR treatment continued to Week 52; patients could continue APR during an open-label, long-term treatment phase for up to 5 years treatment. Visits in years 2, 3, and 4 were scheduled at 13-week intervals. Safety was assessed at each visit throughout the study, and results are summarized here by exposure. Results A total of 1493 patients were randomized and received ≥1 dose of study medication (PBO: n=495; APR30: n=497; APR20: n=501). At the 4-year data cut, the numbers of patients receiving APR30 and APR20 in each exposure period were 1441 in Weeks 0 to ≤52, 1028 in Weeks >52 to ≤104, 865 in Weeks >104 to ≤156, and 767 in Weeks >156 to ≤208. During the 0- to ≤52-week APR-exposure period, adverse events (AEs) occurring in ≥5% of APR30-exposed patients were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis (Table). Most diarrhea and nausea AEs were reported within the first 2 weeks of treatment and usually resolved within 4 weeks; the frequency of gastrointestinal AEs decreased with longer APR30 exposure, and the frequency of other common AEs either decreased or remained stable with prolonged exposure (Table). Most AEs were mild/moderate in severity. During Weeks >156 to ≤208 of APR exposure, the discontinuation rate due to AEs was 1.7% with APR30, and the rate of serious AEs (SAEs) was 7.0%, consistent with earlier periods; most SAEs occurred in 1 patient each. Rates were very low for major cardiac events, malignant neoplasms, and serious opportunistic infections, comparable to the first year of treatment. Rates of depression remained very low in Weeks >156 to ≤208. Marked laboratory abnormalities were infrequent, and most returned to baseline with continued treatment. Conclusions APR30 demonstrated a favorable safety profile and was well tolerated for up to 208 weeks, marked by the lack of accumulation of immunosuppression or need for specific laboratory monitoring. The incidence of AEs remained stable or decreased with long-term exposure to APR30. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Genentech, Janssen, Eli Lilly, Pfizer, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB, Consultant for: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB, J. Gomez-Reino Grant/research support from: Roche and Schering-Plough, Consultant for: BMS, Pfizer, Roche, Schering-Plough, UCB, S. Hall Consultant for: Boehringer Ingelheim, MSD, Roche, Schering-Plough, Servier, Wyeth, Paid instructor for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GSK, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, Wyeth, Speakers bureau: Boehringer Ingelheim, GSK, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, Wyeth, A. Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, Servier, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, UCB, Consultant for: Abbott, Celgene Corporation, Roche, UCB, M. Paris Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, BMS, MSD, Pfizer, UCB, Consultant for: Abbott, BMS, MSD, Pfizer, UCB

FRI0169 Smoking and Response to Rituximab in Anti-CCP Positive and Negative Rheumatoid Arthritis – Results from an International European Collaboration

Background Smoking is a negative predictor of response to antirheumatic therapy. Objectives To assess whether smoking influence the response to rituximab (RTX) in Rheumatoid Arthritis (RA). Methods Pooled data from the Collaborating European Registries for RTX in RA (CERERRA) were used. Patients who received at least 1 cycle with RTX were included. Smoking status was defined as smokers (current smokers) and non-smokers (never and ex-smokers). Analysis of co-variance (ANCOVA) was performed with DeltaDAS28 at 6 months as the dependent variable and smoking status as well as other baseline variables (age, sex, disease duration, number of prior biologic DMARDs) as covariates. Separate analyses were made for anti-CCP positive and negative patients. Results A total of 2274 patients were included - 1815 (80%) non-smokers and 459 (20%) smokers. 81% were female and 80% (out of 1199 patients with available anti-CCP) were anti-CCP positive. Smokers had shorter disease duration than non-smokers (median (IQR) 8 (4-13) years vs. 10 (5-16), p<0.0001), higher number of prior biologic DMARDs (median (IQR) 1 (0-2) vs. 1 (0-1), p<0.0001) and lower DAS28 at baseline (5.3±1.6 vs. 5.8±1.5, p<0.0001). Smokers had less improvement in disease activity than non-smokers at 6 months (mean ± SD DeltaDAS28 -1.5±1.7 vs. -1.8±1.7, respectively, p=0.04). However, the difference was no longer significant after adjustment for baseline differences (p=0.40). When the analysis was stratified by anti-CCP status, smoking did not influence the response to therapy in the anti-CCP negative subset (p=0.39) but there was a trend in the anti-CCP positive subset (p=0.06, figure 1). For the anti-CCP negative patients, 67% of non-smokers and 69% of smokers achieved EULAR response (p=0.6), while in the anti-CCP positive the respective response rates were 76% among non-smokers and 70% among smokers (p=0.09). Conclusions Smoking was negatively associated with the response to rituximab therapy in RA patients who were anti-CCP positive. References Khan A. et al. Smoking, rheumatoid factor status and responses to rituximab. Ann Rheum Dis 2012;71:1587-1588 doi:10.1136/annrheumdis-2012-201758 Saevarsdottir S. et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedis Reumatology register cohorts. Arthritis Rheum 2011;63:26–36. Chatzidionysiou K. et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed. Pooled data from 10 European registries. Ann Rheum Dis 2011;70:1575–80. Disclosure of Interest K. Chatzidionysiou: None declared, E. Lie: None declared, E. Nasonov: None declared, G. Lukina: None declared, M. Hetland: None declared, E. Hauge: None declared, K. Pavelka Consultant for: MSD, AbbVie, Pfizer, Roche, BMS, C. Gabay Grant/research support from: Roche, Merck, Abbvie, Consultant for: Roche, Abbvie, Pfizer, BMS, Sanofi-Aventis, Merck, AB2 Bio, D. Nordström Consultant for: AbbVie, BMS, MSD, Pfizer, Roche, UCB, H. Canhão: None declared, M. Tomsic: None declared, P. van Riel: None declared, J. Gomez-Reino: None declared, I. Ancuta: None declared, T. Kvien: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex, S. Saevarsdottir: None declared

FRI0328 Fixed versus On-Flare Retreatment with Rituximab in RA – Results from the Cererra Collaboration

Background The data on how to optimally retreat patients with RA with rituximab (RTX) have been limited so far. Objectives The aim of this analysis was to compare two common retreatment strategies: A fixed retreatment approach and retreatment when a flare occurs. Methods Pooled data from the Collaborating European Registries for Rituximab in RA (CERERRA) project were used. We identified RA patients who had received at least 2 retreatments (3 courses) with RTX and who had available information about the strategy for retreatment (according to the physicians opinion). The two retreatment strategies were compared by applying an adjusted mixed model analysis with DAS28 improvement as the dependent variable. Results A total of 800 patients were retreated at least twice: 616 patients retreated because of a flare (442 at 1st and 174 at 2nd retreatment) and 184 receiving fixed retreatment (128 at 1st and 56 at 2nd retreatment). Baseline characteristics (incl. age, sex, seropositivity, disease duration, number of prior DMARDs and biologics) at first course of RTX did not differ significantly between the two groups. However, patients retreated on flare had, as expected, a significantly higher DAS28-ESR at the time of 1st retreatment (5.1±1.3 vs. 4.1±1.4, p<0.0001), and a higher HAQ (1.5±0.7 vs. 1.3±0.8, p=0.001). They had also a slightly higher baseline (at the time of RTX start) DAS28 (6.3±1.0 vs. 6.1±1.2, p=0.03). Those retreated on flare were more likely to be treated with corticosteroids (58% vs. 46%, p=0.01) but less likely to receive concomitant DMARDs (82% vs. 92%, p=0.005). The baseline (=start of each cycle) deltaDAS28 (compared to the DAS28 at the time of RTX start) for the two groups is shown in figure 1. Patients receiving fixed retreatment had a significantly higher (in absolute number) deltaDAS28 (p<0.0001) at the start of each cycle, compared to those retreated on-flare. In the adjusted mixed model analysis, we compared the two retreatment groups for the 1st and the 2nd retreatment separately using estimated marginal means. For the 1st retreatment a fixed retreatment yielded significantly better results than the “on-flare”: mean deltaDAS28=-2.4 (95% CI: -3.0; -1.7) vs. -1.8 (95% CI: -3.6; -0.03), p<0.0001. Similar results were found for the 2nd retreatment: mean deltaDAS28=-2.6 (95% CI: -3.1; -2.2) vs. -1.6 (95% CI: -1.8; -1.4), p<0.0001. Conclusions A fixed RTX retreatment strategy in RA seems to be more effective than the retreatment “on-flare” strategy. Disclosure of Interest K. Chatzidionysiou: None declared, E. Lie: None declared, E. Nasonov: None declared, G. Lukina: None declared, M. Hetland: None declared, U. Tarp: None declared, K. Pavelka: None declared, C. Gabay: None declared, D. Nordström: None declared, H. Canhão: None declared, M. Tomsic: None declared, P. van Riel: None declared, J. Gomez-Reino: None declared, I. Ancuta: None declared, T. Kvien Grant/research support: research funding to the Diakonhjemmet Hospital from AbbVie, BMS, MSD/Schering-Plough, Pfizer/Wyeth, Roche and UCB, Consultant for: AbbVie, BMS, Celltrion, Eli Lilly, Hospira, MSD/Schering-Plough, Orion Pharma, Pfizer/Wyeth, Roche, UCB, R. van Vollenhoven: None declared DOI 10.1136/annrheumdis-2014-eular.2571