Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study

Objectives. To assess long-term efficacy, safety and tolerability of secukinumab up to 104 weeks in patients with active PsA. Methods. Patients with PsA (n = 397) were randomized to s.c. secukinumab 300, 150 or 75 mg or placebo at baseline, weeks 1, 2, 3 and 4 and every 4 weeks thereafter. Placebo-treated patients were re-randomized to receive secukinumab 300 or 150 mg s.c. from week 16 (placebo non-responders) or week 24 (placebo responders). Exploratory endpoints at week 104 included 20, 50 and 70% improvement in ACR criteria (ACR20, 50, 70); 75 and 90% improvement in the Psoriasis Area Severity Index, 28-joint DAS with CRP, presence of dactylitis and enthesitis and other patient-reported outcomes. For binary variables, missing values were imputed; continuous variables were analysed by a mixed-effects model for repeated measures. Results. A total of 86/100 (86%), 76/100 (76%) and 65/99 (66%) patients in the secukinumab 300, 150 and 75 mg groups, respectively, completed 104 weeks. At week 104, ACR20 response rates after multiple imputation in the 300, 150 and 75 mg groups were 69.4, 64.4 and 50.3%, respectively. Sustained clinical improvements were observed through week 104 with secukinumab across other clinically important domains of PsA. Responses were sustained through week 104 regardless of prior anti-TNF-a use. Over the entire treatment period the incidence, type and severity of adverse events were consistent with those reported previously. Conclusion. Secukinumab provided sustained improvements in signs and symptoms and multiple clinical domains in patients of active PsA through 2 years of therapy. Secukinumab was well tolerated, with a safety profile consistent with that reported previously. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT0175263

Efficacy and safety of secukinumab administration by autoinjector in patients with psoriatic arthritis: results from a randomized, placebo-controlled trial (FUTURE 3)

Background: The study aimed to assess 52-week efficacy and safety of secukinumab self-administration by autoinjector in patients with active psoriatic arthritis (PsA) in the FUTURE 3 study (ClinicalTrials.gov NCT01989468). Methods: Patients (≥ 18 years of age; N = 414) with active PsA were randomized 1:1:1 to subcutaneous (s.c.) secukinumab 300 mg, 150 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and every 4 weeks thereafter. Per clinical response, placebo-treated patients were re-randomized to s.c. secukinumab 300 or 150 mg at week 16 (nonresponders) or week 24 (responders) and stratified at randomization by prior anti-tumor necrosis factor (TNF) therapy (anti-TNF-naïve, 68.1%; intolerant/inadequate response (anti-TNF-IR), 31.9%). The primary endpoint was the proportion of patients achieving at least 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24. Autoinjector usability was evaluated by Self-Injection Assessment Questionnaire (SIAQ). Results: Overall, 92.1% (300 mg), 91.3% (150 mg), and 93.4% (placebo) of patients completed 24 weeks, and 84.9% (300 mg) and 79.7% (150 mg) completed 52 weeks. In the overall population (combined anti-TNF-naïve and anti-TNF-IR), ACR20 response rate at week 24 was significantly higher in secukinumab groups (300 mg, 48.2% (p < 0.0001); 150 mg, 42% (p < 0.0001); placebo, 16.1%) and was sustained through 52 weeks. SIAQ results showed that more than 93% of patients were satisfied/very satisfied with autoinjector usage. Secukinumab was well tolerated with no new or unexpected safety signals reported. Conclusions: Secukinumab provided sustained improvements in signs and symptoms in active PsA patients through 52 weeks. High acceptability of autoinjector was observed. The safety profile was consistent with that reported previously

Treatment recommendations for psoriatic arthritis

Objective: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. Methods: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. Results: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. Conclusions: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available

Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis. Methods: In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01752634. Findings: Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42–13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25–13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14–4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. Interpretation: Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder

The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS

Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1

OBJECTIVE: To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA). METHODS: Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24. RESULTS: Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05). CONCLUSIONS: In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo

IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy

Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti–IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23–driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes

Safety and Efficacy of Bimekizumab in Patients with Psoriatic Arthritis: 2-Year Results from Two Phase 3 Studies

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1 year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2 years. Methods: BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160 mg every 4 weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40 mg every 2 weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE). Results: A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104 weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100. Conclusions: Bimekizumab was well tolerated for up to 2 years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2 years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms. Trial Registration: BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499)

Bimekizumab treatment in biologic DMARD-naïve patients with active psoriatic arthritis: 52-week efficacy and safety results from the phase 3, randomised, placebo controlled, active reference BE OPTIMAL study

Objectives: Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)‑17F in addition to IL‑17A. BKZ treatment has demonstrated superior efficacy versus placebo (PBO) at Week 16 in biologic disease‑modifying antirheumatic drug (DMARD)‑naïve patients with active psoriatic arthritis (PsA). Here, we report longer‑term efficacy and safety to Week 52. Methods: BE OPTIMAL (NCT03895203) comprised a 16‑week, double‑blind, placebo‑controlled period, then 36 weeks treatment‑blind. Patients were randomised 3:2:1 to subcutaneous BKZ 160 mg every 4 weeks (Q4W), PBO with switch to BKZ at Week 16, or reference arm (adalimumab [ADA] 40 mg Q2W). Efficacy outcomes included the American College of Rheumatology (ACR) response criteria 20/50/70, Psoriasis Area and Severity Index (PASI) 75/90/100 in patients with baseline psoriasis affecting ≥3% body surface area, and minimal disease activity (MDA); non‑responder imputation. Results: ACR20/50/70, PASI75/90/100 and MDA responses were sustained with BKZ to Week 52, consistent with results observed at Week 16. Patients who switched to BKZ at Week 16 demonstrated improvements in efficacy with similar results to BKZ‑randomised patients by Week 52. To Week 52, 555/702 (79.1%) patients had ≥1 treatment-emergent adverse event (TEAE) during BKZ treatment; 113/140 (80.7%) on ADA. On BKZ, 46 (6.6%) patients had serious TEAEs and 1 death (0.1%) occurred. 54 (7.7%) Candida infections occurred during BKZ treatment and 1 (0.7%) during ADA; all cases were localised and non‑serious. Conclusions: The efficacy of bimekizumab in bDMARD-naive patients with PsA was sustained from Week 16 to Week 52. BKZ was well tolerated with no new safety signals observed