To evaluate the effect of ustekinumab (UST), an IL-12/23 p40 inhibitor, on inhibition of progression of structural damage in patients with active psoriatic arthritis (PsA) at wk24 and wk52 in the PSUMMIT 1 and PSUMMIT 2 trials.
Methods
Adult PsA patients with active disease (≥5 SJC and ≥5 TJC; CRP≥0.3mg/dL [ULN 1.0 mg/dL]) despite DMARD and/or NSAID therapy (PSUMMIT 1, n=615; PSUMMIT 2, n=132) or previously treated with DMARD and/or NSAID, and prior anti-TNFα therapy (PSUMMIT 2, n=180) were randomized to UST45mg, 90mg, or PBO at wks 0, 4, and q12wks, thereafter. At wk16, patients with <5% improvement in TJC & SJC entered blinded early escape [EE] (PBO$→ $UST45mg; UST45mg$→ $90mg; 90mg$→ $90mg). No concomitant DMARDs with the exception of MTX (approximately 50% of patients in each study) were permitted. Radiographs of hands and feet were taken at wks 0, 24, and 52 regardless of EE status, or at the time of study drug discontinuation (unless radiographs were completed within the prior 8wks). Erosions and joint space narrowing (JSN) were evaluated by independent readers blinded to treatment, patient IDs and image time sequence using PsA modified van der Heijde-Sharp (vdH-S) method (total score ranging from 0-528). The major secondary endpoint of change from baseline in total vdH-S scores at wk24 was analyzed based on a pre-specified integrated data analysis using data combined from both studies. Imputation of missing data was done using linear extrapolation or median change of 0.
Results
Baseline disease characteristics including total vdH-S, TJC, SJC and CRP were comparable between PSUMMIT 1 & 2. In the integrated analyses, both UST 45 mg and 90 mg treated patients demonstrated a significant difference in change from baseline in total vdH-S scores at wk24 vs PBO (Table). Moreover, continued inhibition was demonstrated through wk 52; patients randomized to PBO who initiated UST at wk16 or 24 demonstrated slowing of radiographic progression by wk52 (mean change in total vdH-S wk24 to wk52 of 0.08). These observations were reproduced when PSUMMIT 1 was evaluated alone. In PSUMMIT 2, a demonstrable effect of UST on inhibition of structural damage progression could not be discerned; these results may have been impacted by missing radiographic data, especially among PBO-treated patients (23% missing radiographs).
Conclusions
Based upon the pre-specified integrated data analysis, ustekinumab inhibits radiographic progression at wk24.
Disclosure of Interest
I. McInnes Grant/research support: Abbott, BMS, Janssen, Pfizer, Roche, Merck/Schering-Plough, and UCB., C. Ritchlin Grant/research support: Amgen, Janssen, and UCB., Consultant for: Abbott, Amgen, Janssen, Regeneron, Roche, and UCB., P. Rahman Grant/research support: Abbott, Amgen, Janssen, Merck/Schering-Plough, and Wyeth., L. Puig Grant/research support: Abbott, Amgen, Celgene, Janssen, Merck/Schering-Plough, and Pfizer., A. Gottlieb Grant/research support: Amgen, Abbott, Celgene, Immune Control, Janssen, Lilly, Novartis, Novo Nordisk, Pfizer, and UCB., Consultant for: Abbott, Actelion, Amgen,Astellas, Belersdorf, BMS, Canfite, Celgene, DemiPsor, Incyte, Janssen, Lilly ICOS, Merck, Novartis, Novo Nordisk, Pfizer, Teva, and UCB., M. Song Employee of: Janssen Research & Development, LLC, B. Randazzo Employee of: Janssen Research & Development, LLC, S. Li Employee of: Janssen Research & Development, LLC, Y. Wang Employee of: Janssen Research & Development, LLC, A. Mendelsohn Employee of: Janssen Research & Development, LLC, A. Kavanaugh Grant/research support: Abbott, Amgen, Janssen, and UCB.
To evaluate long-term clinical/radiographic efficacy of subcutaneous UST 45/90 mg in patients with active psoriatic arthritis (PsA) through wk108 of the PSUMMIT 1 trial.
Methods
Adult PsA pts (n=615) with active disease (≥5 SJC and ≥5 TJC;CRP≥0.3mg/dL) despite DMARD and/or NSAID therapy were randomized to receive UST45mg, 90mg, or PBO at wks 0, 4, and q12wks. At wk16, pts with <5% improvement in TJC & SJC entered blinded early escape (PBO$→ $UST45mg; UST45mg$→ $90mg; 90mg$→ $90mg). PBO-treated patients subsequently crossed over to UST45mg at wk24. Patients received q12wks dosing to wk88, with final efficacy evaluation at wk100 and safety assessment at wk108. Stable concomitant MTX use was permitted but not mandated. Pts treated with prior anti-TNF agents were excluded. Primary endpoint was ACR20 response at wk24. Other efficacy measures included ACR50, 70 responses, changes in HAQ-DI, and changes in vdHS-S scores. Patients who discontinued study agent due to efficacy-related reasons or who initiated protocol-prohibited medications were counted as non-responders. Otherwise, missing data were not imputed. Patients randomized to 45mg group who entered early escape to receive 90mg at wk 16 were included in the 45mg group in analyses.
Results
Through wk108, 79.7% of pts (490/615) completed study agent administration; 20.3% discontinued study agent [including 5.0% for adverse events, and 6.5% for lack of efficacy]. At wk24, significantly larger proportions of UST 45/90 mg pts had ACR20/50/70 responses, and greater improvements in HAQ-DI than PBO patients. Clinical improvements were generally maintained through wk100 (Table). Of 440pts with ≥3% BSA involvement at baseline, 63.9%, 72.5% and 71.3% of PBO$→ $ 45mg, 45mg and 90mg groups achieved PASI 75 at wk100. Wk24 analysis of PSUMMIT 1 demonstrated that UST treatment significantly inhibited radiographic progression at wk24 compared with PBO. Inhibition of radiographic progression was maintained at wk 52 and wk100 (Table). Through wk108, with average follow-up of 91.9 wks, rates (per 100pt-years of f/u) of AEs and serious AEs were 160.60 and 7.10, respectively, in the combined UST group. Rates of serious infections, malignancies, and major adverse cardiovascular events (MACE) were 1.23, 0.38, and 0.66, respectively, in the combined UST-treated group. The proportion of UST injections with injection-site reactions was 0.4%.
Conclusions
In PSUMMIT 1, q12 wk maintenance injections for both UST 45mg and UST 90mg maintained clinical efficacy through wk100. Effects on inhibition of radiographic progression were maintained through wk100. UST continues to be well tolerated and demonstrated a safety profile similar to that seen in PsO patients.
Disclosure of Interest
A. Kavanaugh Grant/research support: Abbott, Amgen, Janssen, and UCB., L. Puig Grant/research support: Abbott, Amgen, Celgene, Merck/Schering-Plough, and Pfizer., A. Gottlieb Grant/research support: Amgen, Abbott, Celgene, Immune Control, Janssen, Lilly, Novartis, Novo Nordisk, Pfizer, and UCB., Consultant for: Abbott, Actelion, Amgen, Astellas, Belersdorf, BMS, Canfite, Celgene, DemiPsor, Incyte, Janssen, Lilly ICOS, Merck, Novartis, Novo Nordisk, Pfizer, Teva, and UCB., C. Ritchlin Grant/research support: Amgen, Janssen, and UCB., Consultant for: Abbott, Amgen, Janssen, Regeneron, Roche, and UCB., S. Li Employee of: Janssen Research & Development, LLC., Y. Wang Employee of: Janssen Research & Development, LLC., A. Mendelsohn Employee of: Janssen Research & Development, LLC., M. Song Employee of: Janssen Research & Development, LLC., P. Rahman Grant/research support: Abbott, Amgen, Janssen, Merck/Schering-Plough, and Wyeth., I. McInnes Grant/research support: Abbott, BMS, Janssen, Pfizer, Roche, Merck/Schering-Plough, and UCB.
Objective:To use data from a phase II clinical trial to evaluate the effect of ustekinumab, a human immunoglobulin monoclonal antibody that binds with high affinity to the shared p40 subunit of human interleukins-12 and -23, on physical disability and health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA).Methods:In this multicenter, double-blind, placebo-controlled, crossover study of ustekinumab, patients with active PsA were randomized (1:1 ratio) to receive either ustekinumab at weeks 0, 1, 2, and 3 and placebo at weeks 12 and 16 (n = 76) or placebo at weeks 0, 1, 2, and 3 and ustekinumab at weeks 12 and 16 (n = 70). Physical function was assessed using the disability index from the Health Assessment Questionnaire-Disability Index (HAQ-DI) in all randomized patients. HRQoL was evaluated using the Dermatology Life Quality Index (DLQI) in a subset of patients (84.9%) with at least 3% body surface area (BSA) psoriasis involvement at baseline.Results:At baseline, overall mean HAQ-DI and DLQI scores were 0.9 and 11.5, respectively, indicating impaired physical function and moderate effect on HRQoL. At week 12, ustekinumab patients had significantly more improvement (decrease) in the mean HAQ-DI (−0.31) and DLQI (−8.6) scores versus placebo (−0.04 and −0.8, respectively; p < 0.001 for both comparisons). At week 12, 58.7% (37/63) of ustekinumab-treated patients had a DLQI score of 0 or 1 (no negative effect of disease or treatment on HRQoL) versus 5.5% (3/55) for placebo (p < 0.001). The results also indicated a positive but weak correlation between improvement in physical function and HRQoL, pain, and skin response as well as between improvement in joint and skin responses in patients receiving ustekinumab or placebo. Potential limitations of the study include the short duration of the placebo-controlled period and the relatively small patient population.Conclusion:Ustekinumab significantly improved physical function and HRQoL in patients with PsA and psoriasis involving at least 3% BSA.
