Background: Biologic disease modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis (r-axSpA), otherwise known as ankylosing spondylitis, when conventional therapies fail. We report efficacy and safety results of a Phase 3 study of ixekizumab, a high-affinity monoclonal antibody that selectively targets IL-17A, in bDMARDnaïve patients with r-axSpA. Methods: In this randomized, double-blind, Phase 3 study, adult patients with inadequate response/intolerance to NSAIDs, an established diagnosis of r-axSpA, and with radiographic sacroiliitis centrally defined by modified New York criteria and ≥1 spondyloarthritis feature according to Assessment of Spondyloarthritis International Society (ASAS) criteria were recruited from 84 sites (12 countries) in Europe, Asia, and North America. Patients were randomized 1:1:1:1 using a computer-generated random sequence to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference arm), or placebo. The primary endpoint was the proportion of patients achieving an ASAS40 response at Week 16. Findings: Between June 20, 2016 and August 22, 2017, 341 patients were randomized to placebo (N=87), adalimumab (N=90), ixekizumab Q2W (N=83), or ixekizumab Q4W (N=81). At Week 16, significantly more patients achieved ASAS40 with ixekizumab Q2W (n=43, 51•8%, p<0•0001), ixekizumab Q4W (n=39, 48•1%, p<0•0001), and adalimumab (n=32, 35•6%; p=0•0053) versus placebo (n=16, 18•4%). One serious infection occurred in each of the ixekizumab Q2W (1•2%), ixekizumab Q4W (1•2%), and adalimumab (1•1%) arms; none were reported with placebo. One (1•1%) Candida infection occurred in the adalimumab arm and one (1•2%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn's disease. No opportunistic infections, malignancies, or deaths occurred. Interpretation: Each dosing regimen of ixekizumab was superior to placebo for improving r-axSpA signs and symptoms in bDMARD-naïve patients; the safety profile was consistent with previous studies of ixekizumab. The adalimumab control arm performed as expected. Funding: Eli Lilly and Company Research in context Evidence before this study Pubmed was searched using the terms "ankylosing spondylitis", "axial spondyloarthritis", and "disease-modifying anti-rheumatic drugs", including articles through May 30, 2018. Axial spondyloarthritis (axSpA) is a chronic immune-mediated disease characterized by inflammation of the spine and sacroiliac joint (SIJ), peripheral joint involvement, extra articular manifestations, and a strong genetic association with human leukocyte antigen (HLA)-B27. Radiographic axSpA (r-axSpA) was previously classified as ankylosing spondylitis (AS) in 1984 and updated to r-axSpA as part of the ASAS criteria. Both criteria sets require the same radiographically confirmed structural damage to the sacroiliac joint as well as at least one accompanying clinical element. Recommendations for the management of r-axSpA generally include exercise and physiothera...

ObjectiveTo assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of rheumatoid arthritis (RA).MethodsIn this 12-week, double-blind, placebo-controlled study, patients with active RA (n=350) were randomised 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing RA disease-modifying antirheumatic drug (DMARD) treatment. The primary end point was the percentage of patients achieving a 20% improvement in RA signs and symptoms according to American College of Rheumatology criteria (ie, an ACR20 response) at week 12. Changes in morning pain, duration of morning stiffness, 28-joint Disease Activity Score and health-related quality of life were also assessed.ResultsMR prednisone plus DMARD treatment produced higher response rates for ACR20 (48% vs 29%, p<0.001) and ACR50 (22% vs 10%, p<0.006) and a greater median relative reduction from baseline in morning stiffness (55% vs 35%, p<0.002) at week 12 than placebo plus DMARD treatment. Significantly greater reductions in severity of RA (Disease Activity Score 28) (p<0.001) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score) (p=0.003) as well as a greater improvement in physical function (36-item Short-Form Health Survey score) (p<0.001) were seen at week 12 for MR prednisone versus placebo. The incidence of adverse events was similar for MR prednisone (43%) and placebo (49%).ConclusionLow-dose MR prednisone added to existing DMARD treatment produced rapid and relevant improvements in RA signs and symptoms.ClinicalTrials.gov, numberNCT00650078

Background:This first-in-human, phase I clinical trial of p28 (NSC745104), a 28-amino-acid fragment of the cupredoxin azurin, investigated the safety, tolerability, pharmacokinetics and preliminary activity of p28 in patients with p53+ metastatic solid tumours.Methods:A total of 15 patients were administered p28 i.v. as a short infusion three times per week for 4 weeks followed by a 2-week rest under an accelerated titration 3+3 dose escalation design until either a grade 3-related adverse event occurred or the maximum tolerated dose (MTD) was reached. Single-dose and steady-state serum pharmacokinetics were characterised. Assessments included toxicity, best objective response by RECIST 1.1 Criteria, and overall survival.Results:No patients exhibited any dose-limiting toxicities (DLTs), significant adverse events or exhibited an immune response (IgG) to the peptide. The No Observed Adverse Effect Level (NOAEL) and MTD were not reached. Seven patients demonstrated stable disease for 7–61 weeks, three a partial response for 44–125 weeks, and one a complete response for 139 weeks. Three patients are still alive at 158, 140, and 110 weeks post therapy completion.Conclusion:p28 was tolerated with no significant adverse events. An MTD was not reached. Evidence of anti-tumour activity indicates a highly favourable therapeutic index and demonstrates proof of concept for this new class of non-HDM2-mediated peptide inhibitors of p53 ubiquitination.

Heparin-induced thrombocytopenia and thrombosis is associated with a significant incidence of morbidity and mortality. Prompt recognition of this complication and immediate withdrawal of heparin therapy are imperative. This report describes a case of heparin-induced thrombosis and thrombocytopenia with major vascular insufficiency of the extremities. This is the first reported instance of the use of intravenous streptokinase for the treatment of heparin-induced venous thrombosis.

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