ObjectiveTo evaluate risankizumab, a biological therapy that inhibits interleukin 23, in patients with active psoriatic arthritis (PsA) who have responded inadequately or are intolerant to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD).MethodsIn the randomised, placebo-controlled, double-blind KEEPsAKE 1 trial, 964 patients with active PsA were randomised (1:1) to receive risankizumab 150 mg or placebo at weeks 0, 4 and 16. The primary endpoint was the proportion of patients achieving ≥20% improvement in American College of Rheumatology criteria (ACR20) at week 24. Here, we report the results from the 24-week double-blind period; the open-label period with all patients receiving risankizumab is ongoing.ResultsAt week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (57.3% vs placebo, 33.5%; p<0.001). Significant differences were also observed for risankizumab versus placebo for the first eight ranked secondary endpoints, including skin and nail psoriasis endpoints, minimal disease activity and resolution of enthesitis and dactylitis (p<0.001). Adverse events and serious adverse events were reported at similar rates in the risankizumab and placebo groups. Serious infections were reported for 1.0% and 1.2% of patients receiving risankizumab and placebo, respectively. There was one death in the risankizumab group (urosepsis deemed unrelated to the study drug).ConclusionsRisankizumab treatment results in significantly greater improvement of signs and symptoms of PsA compared with placebo and is well tolerated in patients with active PsA who have responded inadequately or are intolerant to ≥1 csDMARD.Trial registration numberNCT03675308.

ObjectivesRisankizumab is an interleukin-23 inhibitor under study for the treatment of patients with psoriatic arthritis (PsA). The phase 3 KEEPsAKE 2 trial investigated the efficacy and safety of risankizumab versus placebo in patients with active PsA who had previous inadequate response or intolerance to ≤2 biological therapies (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). Results through week 24 are reported here.MethodsAdults with PsA who were Bio-IR and/or csDMARD-IR were randomised to receive subcutaneously administered risankizumab 150 mg or placebo at weeks 0, 4 and 16 during a 24-week, double-blind treatment period. The primary endpoint was the proportion of patients who achieved ≥20% improvement in American College of Rheumatology score (ACR20) at week 24. Secondary endpoints assessed key domains of PsA and patient-reported outcomes.ResultsA total of 444 patients (median age 53 years, range 23–84 years) were randomised to risankizumab (n=224) or placebo (n=220); 206 patients (46.5%) were Bio-IR. At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (51.3% vs 26.5%, p<0.001) and all secondary endpoints (p<0.05) compared with placebo. Serious adverse events were reported for 4.0% and 5.5% of risankizumab-treated and placebo-treated patients, respectively; serious infections were reported for 0.9% and 2.3%, respectively.ConclusionTreatment with risankizumab resulted in significant improvements versus placebo in key disease outcomes and was well tolerated in patients with PsA who were Bio-IR and/or csDMARD-IR.Trial registration numberNCT03671148.

BackgroundInterleukin-23 (IL-23), a key regulator of multiple effector cytokines, has been implicated in the pathogenesis of psoriatic lesions, synovitis, enthesitis, and bone erosion. Risankizumab (RZB) is a humanised IgG1 monoclonal antibody that binds to p19 subunit of IL-23, selectively inhibiting this critical cytokine.ObjectivesTo report the efficacy and safety of different doses of RZB in patients (pts) with active psoriatic arthritis (PsA) over 24 weeks.MethodsIn this double-blind, parallel-design, dose-ranging Phase 2 study, pts with active PsA (stratified by prior TNFi use and concurrent MTX use) were randomised in a 2:2:2:1:2 ratio to receive RZB (150 mg at weeks [Wks] 0, 4, 8, 12, and 16 [Arm 1], 150 mg at Wks 0, 4, and 16 [Arm 2], 150 mg at Wks 0 and 12 [Arm 3], 75 mg single dose at Wk 0 [Arm 4]) or matching placebo (PBO, Arm 5). Pts completing Wk 24 visit had an option to enter a separate open-label extension (OLE) study; pts not entering the OLE were followed until Wk 32. Efficacy assessments included ACR20/50/70, PASI, minimal disease activity (MDA), DAS28(CRP), dactylitis count, SPARCC enthesitis index, pain-VAS, HAQ-DI, and mTSS scores.ResultsOf the 185 pts who received the study drug, 173 (93.5%) completed 16 Wks of treatment and 145 (78.4%) entered OLE at Wk 24. The primary endpoint of ACR20 response at Wk 16 was achieved by pts in each of the RZB arms.1 At Wk 24, ACR20/50/70 responses were significantly higher in pts receiving RZB (pooled across all RZB arms) compared with PBO (table 1). PASI75/90/100 responses at Wk 24 were significantly higher in RZB-treated pts compared with PBO. At Wk 24, RZB-treated pts achieved significantly higher MDA responses as well as greater improvements in DAS28(CRP) and Pain–VAS. Improvements in HAQ-DI and enthesitis from BL were numerically greater in RZB arms. At Wk 24, RZB-treated pts (pooled across all RZB arms) showed significant improvement from BL in mTSS compared with PBO. Treatment-emergent adverse events (TEAEs), collected up to Wk 32, were comparable across treatment arms (table 2); the most common TEAE was infection. There were no deaths or cases of tuberculosis in RZB-treated pts; 2 adjudicated major adverse cardiovascular events were reported in RZB arms.Abstract OP0307 – Table 1Summary of efficacy results at week 24*Abstract OP0307 – Table 2Overview of treatment-emergent adverse events (TEAEs) over 32 weeksConclusionsPts with active PsA treated with RZB maintained improvement in joint and skin symptoms through 24 wks. RZB-treated pts (pooled across all RZB arms) showed evidence for inhibition of radiographic progression. RZB was well-tolerated with no new or unexpected safety findings.Reference[1] Mease PJ, et al. Arthritis Rheumatol2017;69(suppl 10).AcknowledgementsAbbVie and Boehringer Ingelheim (BI) funded the study (NCT02719171); BI contributed to its design and participated in data collection and both participated in data analysis and interpretation of the data, and in writing, review, and approval of the publication. AbbVie, BI, and the autho...

Grb2-associated binder 1 (GAB1) is a docking protein found to associate with the activated c-MET receptor via the MET-binding domain (MBD) and appears to be critical for the tubulogenic actions of this receptor. Pulldown experiments with bacterially expressed MBD and full-length GAB1 revealed the presence of c-MET as well as phosphorylated ERK2 (pERK2). By using purified pERK2 and non-pERK2, we found that GAB1 associates exclusively with the phosphorylated form of the enzyme and that this association does not require mediation by a third protein. When epitope-tagged GAB1 was cotransfected with constitutively active MEK1 into A293 cells, co-immunoprecipitation of GAB1 and pERK2 was observed, demonstrating that this interaction can occur in intact cells. In vitro, both the MBD and full-length GAB1 were found to be substrates for activated ERK2. In intact cells, epitope-tagged GAB1 was found to be basally phosphorylated on serine with an increase following co-transfection with constitutively active MEK1 and the appearance of novel phosphorylation sites detected by phosphopeptide mapping. Thus, it appears that GAB1 can associate directly with phosphorylated ERK2 via the MET-binding domain and that GAB1 then acts as a substrate for the enzyme.In cultured epithelial cells, the tyrosine kinase receptor c-MET and its ligand hepatocyte growth factor (HGF) 1 are capable of inducing mitogenesis, motogenesis (scattering/chemotaxis), and morphogenesis (formation of branching tubules) (1). In the kidney, these distinct actions may comprise the components of more complex events such as ureteric bud branching and repair of renal tubules after injury. Whereas mitogenesis and motogenesis have been described following activation of many tyrosine kinase receptors, epithelial tubulogenesis appears to be relatively specific for ligand activation of members of the MET receptor family and the epidermal growth factor receptor (EGFR) family (2). Recently a docking protein, GAB1 (Grb-2-associated binding protein 1), was found to associate with both c-MET and the EGFR in a ligand-dependent fashion and to be capable of inducing the tubulogenic phenotype (3-5).GAB1 was cloned by as a protein that associated with Grb-2 in an expression library assay. The amino acid sequence of GAB1 suggested that it was a docking protein similar to the insulin receptor substrate 1 family with an amino-terminal pleckstrin homology (PH) domain and a proline-rich carboxyl terminus, as well as tyrosine phosphorylation sites for potential SH2 binding by the phosphoinositide 3-kinase, Grb2, phospholipase C-␥, and SHPTP2. By using a yeast two-hybrid screen with the carboxyl terminus of c-MET as the bait, Weidner et al. (4), and Grb-2-mediated interaction between the proline-rich region of GAB1 and Y 1356 VNV of c-MET (6). The finding that the MBD of GAB1 associates directly with c-MET in a tyrosine-dependent fashion suggests that this domain might associate with other tyrosine-phosphorylated proteins and thus act in a novel fashion to mediate epithelial signaling ...

BackgroundPatients undergoing cardiac surgeries with cardiopulmonary bypass (on‐pump) have a high risk for acute kidney injury (AKI). We tested ABT‐719, a novel α‐melanocyte‐stimulating hormone analog, for prevention of AKI in postoperative cardiac surgery patients.Methods and ResultsThis phase 2b randomized, double‐blind, placebo‐controlled trial included adult patients with stable renal function undergoing high‐risk on‐pump cardiac surgery in the United States and Denmark. Participants received placebo (n=61) or cumulative ABT‐719 doses of 800 (n=59), 1600 (n=61), or 2100 μg/kg (n=59). Primary outcome was development of AKI based on Acute Kidney Injury Network (AKIN) criteria, measured utilizing preoperative creatinine value and maximum value within 48 hours and urine output within the first 42 hours postsurgery. Secondary outcomes included incidence of AKI based on maximal changes from baseline in novel AKI biomarkers over a 72‐hour period after clamp release and length of intensive care unit stays through 90 days postsurgery. A total of 65.5%, 62.7%, and 69.6% of patients in the 800‐, 1600‐, and 2100‐μg/kg groups, respectively, developed AKI (stages 1, 2, and 3 combined) versus 65.5% in the placebo group (for each pair‐wise comparison with placebo, P=0.966, 0.815, and 0.605, respectively). Adverse events occurred at a similar rate in all treatment groups.Conclusions ABT‐719 treatment did not lower AKI incidence using AKIN criteria, influence the elevations of novel biomarkers, or change 90‐day outcomes in patients after cardiac surgery.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01777165.