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Objectives Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. Methods COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. Results During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P  = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (−73.79% and −47.96%, P  = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. Conclusions SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. Clinical trial registration NCT03905512. [ABSTRACT FROM AUTHOR]

Objective To evaluate the long-term safety and efficacy of sarilumab with/without conventional synthetic (cs)DMARDs in RA. Methods The analyses evaluated two open-label extensions (OLEs): EXTEND and MONARCH OLE, which included patients from six randomized trials. Patients received sarilumab 200 mg once every 2 weeks (q2w) for at least 264 weeks up to 516 weeks (EXTEND: Sarilumab Monotherapy and Sarilumab + csDMARD groups) or for 276 weeks (MONARCH OLE: Continuation and Switch groups). Primary endpoints included safety, immunogenicity and changes in laboratory parameters. Secondary endpoints included clinical signs and symptoms along with health-related quality-of-life (HRQOL) questionnaires. Results The Sarilumab Monotherapy (n  =   111), Continuation (n  =   165) and Switch (n  =   155) groups received sarilumab monotherapy, while the Sarilumab + csDMARD group (n  =   1910) received sarilumab in combination with csDMARDs. Incidence of one or more treatment-emergent adverse events was 126 (Sarilumab Monotherapy group), 169 (Sarilumab + csDMARD group), 159 (Continuation group) and 159 (Switch group) events/100 patient-years. Neutropenia was the most common adverse event. Neutropenia was not associated with an increased incidence of infections. Most neutropenia cases normalized on-treatment. Adverse events of special interests, such as malignancies, major adverse cardiovascular events, venous thromboembolism and gastrointestinal perforations, were rare. Immunogenicity was low and not associated with hypersensitivity reactions or discontinuations due to lack or loss of efficacy. Improvements in clinical signs and symptoms and HRQOL, observed during the initial blinded trials, were maintained throughout the OLE assessment period. Conclusions Long-term sarilumab treatment with/without csDMARDs in patients with RA revealed no new safety findings. Efficacy and HRQOL were maintained or further increased over the open-label assessment period. Trial registration EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652 , NCT01146652; MONARCH OLE, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02332590 , NCT02332590 [ABSTRACT FROM AUTHOR]

Objective: To assess the long‐term safety, tolerability, and efficacy of bimekizumab in patients with active ankylosing spondylitis (AS). Methods: Patients with active AS who completed the dose‐ranging, 48‐week BE AGILE randomized controlled trial were eligible to participate in an open‐label extension (OLE) study, in which patients received 160 mg of bimekizumab every 4 weeks. We present the safety and efficacy results through 156 weeks. Missing efficacy data were imputed using nonresponder imputation analysis for binary outcomes and multiple imputation for continuous outcomes. Results: From weeks 0–156, 280 of 303 patients (exposure‐adjusted incidence rate 141.0 per 100 patient‐years) experienced ≥1 treatment‐emergent adverse event; the most frequent adverse events were nasopharyngitis (8.1 per 100 patient‐years) and upper respiratory tract infection (5.0 per 100 patient‐years). Additionally, 67 of 303 patients (9.8 per 100 patient‐years) had mild to moderate localized fungal infections (28 of 303 patients had Candida infections [3.7 per 100 patient‐years] and 23 of 303 patients had oral candidiasis [3.0 per 100 patient‐years]), 10 patients had serious infections (1.3 per 100 patient‐years), and no cases of active tuberculosis were reported. Active inflammatory bowel disease (1.1 per 100 patient‐years), anterior uveitis (0.7 per 100 patient‐years), and adjudicated major adverse cardiovascular events (0.3 per 100 patient‐years) were infrequent. The efficacy of bimekizumab treatment demonstrated at week 48 was sustained in the OLE study. At week 156, nonresponder imputation analysis showed that 53.7% of patients (72.6% of observed cases) met the Assessment of SpondyloArthritis international Society criteria for 40% improvement and 28.0% of patients (37.9% of observed cases) achieved partial remission; Ankylosing Spondylitis Disease Activity Scores were reduced from baseline (mean ± SEM 3.9 ± 0.1) to week 48 (2.1 ± 0.1) and week 156 (1.9 ± 0.1) (multiple imputation). Patients showed sustained improvements in pain, fatigue, physical function, and health‐related quality of life. Conclusion: The safety profile of bimekizumab was found to be consistent with previously demonstrated findings, and no new safety signals were identified. The efficacy of bimekizumab in patients with AS was sustained through 3 years of treatment. Video Abstract [ABSTRACT FROM AUTHOR]

Objective: To assess the safety and biological activity of rozibafusp alfa, a first‐in‐class bispecific antibody–peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). Methods: This phase 1b, double‐blind, placebo‐controlled, multiple ascending dose study included 34 patients (18–75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints–C‐reactive protein [DAS28‐CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow‐up. The primary end point was the incidence of treatment‐emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28‐CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease). Results: TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t1/2 = 4.6–9.5 days) and dose‐related, reversible PD (>90% ICOSL receptor occupancy in 210‐ and 420‐mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti–rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210‐ and 420‐mg cohorts. Conclusion: Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease. [ABSTRACT FROM AUTHOR]

Objectives Apremilast monotherapy was evaluated up to 5 years in PALACE 4 (fourth PsA Long-term Assessment of Clinical Efficacy study) DMARD-naïve patients with PsA. Methods Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg or apremilast 20 mg twice a day. Placebo patients were rerandomized to apremilast at week 16 or 24. Double-blind apremilast continued to week 52, with a 4-year open-label extension (≤260 weeks of exposure). Analyses through week 260 were based on observed data. Results A total of 527 patients were treated. Among patients randomized to apremilast 30 mg at baseline, 45.5% completed week 260. At study end, 24.8% reported conventional synthetic DMARD or steroid use for any reason. At week 260, 65.8%/39.0%/20.3% of apremilast 30 mg patients achieved ACR20/ACR50/ACR70 responses, respectively. PsA sign and symptom improvements were sustained up to week 260 with continued treatment, including reductions in swollen (84.8%) and tender (76.4%) joint counts. Among apremilast 30 mg patients with baseline enthesitis or dactylitis, 71.2% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 95.1% achieved a dactylitis count of 0. Over 50% of patients achieved a HAQ Disability Index minimal clinically important difference (≥0.35). In patients with ≥3% baseline psoriasis-involved body surface area, 60.3% and 47.6% achieved ≥50% and ≥75% improvement in Psoriasis Area and Severity Index scores, respectively. Patients continuing apremilast 20 mg also demonstrated consistent, sustained improvements. The most common adverse events were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. No new safety concerns were observed long term. Conclusions Apremilast led to sustained PsA efficacy up to 260 weeks and was well tolerated. Trial registration ClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423. [ABSTRACT FROM AUTHOR]

Objective: To report the primary (1‐year) results from PREVENT, the first phase III study evaluating secukinumab in patients with active nonradiographic axial spondyloarthritis (SpA). Methods: A total of 555 patients were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with a loading dose (loading dose [LD] group), secukinumab 150 mg without a loading dose (non–loading dose [NL] group), or placebo weekly and then every 4 weeks starting at week 4. The NL group received placebo at weeks 1, 2, and 3 to maintain blinding. Switch to open‐label secukinumab or standard of care was permitted after week 20. The study had 2 independent analysis plans, per European Union and non‐US (plan A; week 16) and US (plan B; week 52) regulatory requirements. The primary end point was 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society (ASAS40) criteria at week 16 (in the LD group) and at week 52 (in the NL group) in tumor necrosis factor inhibitor (TNFi)–naive patients. Safety analyses included all patients who received ≥1 dose of study treatment. Results: Overall, 481 patients completed 52 weeks of treatment, including 84.3% (156 of 185) in the LD group, 89.7% (165 of 184) in the NL group, and 86.0% (160 of 186) in the placebo group. The proportion of patients who switched to open‐label or standard of care between weeks 20 and 48 was 50.8% in the LD group, 47.3% in the NL group, and 64.0% in the placebo group. Both primary and all secondary end points were met at week 16. The proportion of TNFi‐naive patients who met ASAS40 was significantly higher for LD at week 16 (41.5%) and NL at week 52 (39.8%) versus placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05). No new safety findings were reported. Conclusion: Our findings indicate that secukinumab 150 mg provides significant and sustained improvement in signs and symptoms of nonradiographic axial SpA through 52 weeks. Safety was consistent with previous reports. [ABSTRACT FROM AUTHOR]

Objective. The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods. RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results. Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion. In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96weeks were sustained through 4 years of treatment, with no new safety signals. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with limited conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with moderate-to-severe rheumatoid arthritis (RA). Methods In this randomized, double-blind, phase IIb trial, patients with RA (n = 289) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg or matching placebo once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. Results ACR20 response rates at week 12 were 22.0%, 36.8%, 48.3% ( P < 0.05), 56.3% ( P < 0.01), and 29.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Patients in the peficitinib 100 mg and 150 mg groups achieved a rapid and statistically significant ACR20 response compared with those in the placebo group ( P < 0.05), reaching statistical significance by week 2. Overall, the incidence of adverse events (AEs) was similar between patients receiving peficitinib and those receiving placebo. The most common AEs were upper respiratory tract infection (5% [n = 15]), nausea (4% [n = 12]), and urinary tract infection (4% [n = 10]). There was 1 case of herpes zoster in the placebo group, and 1 serious infection (limb abscess) in the peficitinib 25 mg group. There were no incidences of grade 2 or higher neutropenia or lymphopenia. Conclusion In patients with moderate-to-severe RA, orally administered once-daily peficitinib in combination with limited csDMARDs resulted in a dose-dependent ACR20 response rate over 12 weeks with satisfactory tolerability. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Methods Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52. Results Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [ P < 0.0001]; least squares mean change in HAQ DI at week 16, −0.53, −0.55, and −0.29, respectively [ P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [ P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 109/liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 109/liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts. Conclusion In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade. [ABSTRACT FROM AUTHOR]

Objective To assess the efficacy and safety of oral decernotinib (VX-509; Vertex Pharmaceuticals) monotherapy in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study of patients with rheumatoid arthritis (RA). Methods Two hundred four adults with active RA who had been unsuccessfully treated with ≥1 disease-modifying antirheumatic drug were administered placebo tablets or decernotinib twice a day at dosages of 25 mg, 50 mg, 100 mg, or 150 mg. Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and mean change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Results At week 12, the ACR20 response rates were 39.0%, 61.0%, 65.0%, and 65.9% in the 25-mg, 50-mg, 100-mg, and 150-mg groups, respectively, and were significantly higher in the 50-mg group ( P = 0.007) and the 100-mg and 150-mg groups ( P = 0.002) as compared to the response rates in the placebo group (29.3%). The mean change from baseline in DAS28-CRP was greater in the 50-mg, 100-mg, and 150-mg groups as compared to the placebo group ( P < 0.001). Decernotinib treatment resulted in higher ACR50 and ACR70 response rates, more patients with DAS28-CRP scores <2.6, and improvements in the Health Assessment Questionnaire disability index as compared to placebo. The most common adverse events in any decernotinib group were nausea (6.1%), headache (4.3%), an increase in levels of alanine aminotransferase (4.3%), and hypercholesterolemia (3.7%). In the groups receiving decernotinib, there was an increased risk of infections and increased liver transaminase levels. Conclusion Decernotinib was efficacious in improving clinical signs and symptoms of RA at week 12 at dosages of 50-150 mg twice a day. Infections and increases in liver transaminase and lipid levels were noted as potential safety signals. [ABSTRACT FROM AUTHOR]

Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation. [ABSTRACT FROM AUTHOR]

Background/Purpose: The long-term efficacy and safety of intravenous abatacept in patients (pts) with juvenile idiopathic arthritis (JIA) have been reported previously from the Phase III AWAKEN trial (). Here, we report efficacy, safety and pt-reported outcomes from the open-label, long-term extension (LTE) of AWAKEN, with up to 7 years of follow-up. Methods: Pts entered the LTE if they were JIA ACR 30 non-responders (NR) at the end of the 4-month lead-in period (abatacept only), or if they received abatacept or placebo (pbo) in the 6-month double-blind (DB) period. The Child Health Questionnaire was used to evaluate health-related quality of life (HRQoL); physical (PhS) and psychosocial (PsS) summary and pain scores were analyzed. Pain was assessed by parent global assessment using a 100 mm visual analog scale. Efficacy and HRQoL evaluations are reported up to Day 1765 (~ Year 5.5). Safety is presented for the cumulative period (lead-in, DB and LTE), for all pts who received abatacept during the LTE. Results: Of the 153 pts entering the LTE (58 from DB abatacept group, 59 from DB pbo group, 36 NR), 69 completed the trial (29 abatacept, 27 pbo, 13 NR). For pts treated in the LTE, mean (range) exposure to abatacept was 53.6 (5.6-85.6) months. During the LTE, incidence rates of AEs and serious AEs per 100 pt-years were 209.1 and 5.6. Thirty pts (19.6%) had serious AEs; most were unrelated and were musculoskeletal (8.5%) or infectious events (6.5%). No malignancy was reported. There was one death (accidental; unrelated). At Day 169, JIA ACR 50 and 70 response rates were 79.3% and 55.2% in the abatacept group, and 52.5% and 30.5% in the pbo group; 31.0% and 10.2% of pts in the abatacept and pbo groups, respectively, had inactive disease. By Day 1765, JIA ACR 50 and 70 response rates were 93.9% and 78.8% in the abatacept group, and 80.0% and 63.3% in the pbo group; 51.5% and 33.3% had inactive disease. In the NR group, 69.2% and 53.8% of pts achieved JIA ACR 50 and 70 responses at Day 1765, and 30.8% had inactive disease. In pts who entered the LTE, mean baseline PhS scores were below the range for healthy children (abatacept 30.2, pbo 31.0, NR 29.5). At Day 169, 38.3% of pts had reached a PhS score >50 ((). By the end of the LTE, 43.5% of pts had reached a PhS score >50. At baseline, mean PsS scores for those who entered the LTE were slightly lower than the mean for healthy children (abatacept 43.5, pbo 44.2, NR 47.0). At Day 169, 54.9% of pts had a PsS score >50 (). By Day 1765, 58.1% of pts had reached a PsS score >50. At baseline, the mean pain score was 42.9. By Day 169, 13.9% of pts were considered pain free (pain score = 0); this was maintained over the LTE (). [ABSTRACT FROM AUTHOR]