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This trial compared the combination of abciximab and unfractionated heparin with bivalirudin in patients with non–ST-segment elevation MI who were undergoing coronary stenting. The two regimens had similar efficacy, but there was more bleeding with abciximab and heparin. An invasive strategy of coronary angiography, with revascularization when appropriate, is recommended for high-risk patients who have an acute coronary syndrome. 1 , 2 Owing to the key role that the rupture of an atherosclerotic plaque, which is highly prothrombotic, plays in the pathogenesis of these syndromes, 3 identifying the most appropriate adjunctive antithrombotic therapy before, during, and after percutaneous coronary intervention (PCI) has been the target of extensive research for the past three decades. Abciximab is a glycoprotein IIb/IIIa inhibitor with potent platelet-antiaggregative effects. 4 Although the administration of abciximab during PCI was not associated with a clinical benefit in patients in stable . . .

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia–Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0−71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25−0·61]; p<0·0001). 31 (27·9% [19·6–36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3–63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. argenx.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, at the end of 2019, and there are currently no specific antiviral treatments or vaccines available. SARS-CoV-2 has been shown to use the same cell entry receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In this report, we generate a recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1. A fusion protein containing an ACE2 mutant with low catalytic activity is also used in this study. The fusion proteins are then characterized. Both fusion proteins have a high binding affinity for the receptor-binding domains of SARS-CoV and SARS-CoV-2 and exhibit desirable pharmacological properties in mice. Moreover, the fusion proteins neutralize virus pseudotyped with SARS-CoV or SARS-CoV-2 spike proteins in vitro. As these fusion proteins exhibit cross-reactivity against coronaviruses, they have potential applications in the diagnosis, prophylaxis, and treatment of SARS-CoV-2. SARS-CoV-2 uses ACE2 as the entry receptor. Here, the authors show that an ACE2-Ig fusion protein inhibits entry of virus pseudotyped with the SARS-CoV-2 spike protein, show differential binding kinetics of SARS-CoV and SARSCoV-2 spike proteins to ACE2, and determine pharmakocinetic parameters of ACE2-Ig in mice.

Objective The objective of this paper is to investigate the safety, pharmacokinetics (PK) and immunogenicity of CDP7657, a PEGylated anti-CD40L antibody fragment, in healthy individuals and patients with systemic lupus erythematosus (SLE). Methods This randomized, double-blind, single-dose, dose-escalation phase I study consisted of two parts. In part 1, 28 healthy individuals received CDP7657 IV (0.004–5 mg/kg) or placebo. In part 2, 17 patients with SLE received CDP7657 IV (5–60 mg/kg) or placebo. The CDP7657:placebo ratio was 3:1. Results Adverse events (AEs) were reported by 76% of healthy individuals and 100% of patients with SLE treated with CDP7657; most were mild or moderate in intensity. Two healthy individuals reported serious AEs (SAEs), one of which was considered treatment related (infusion-related reaction; 5 mg/kg cohort). One patient with SLE (60 mg/kg cohort) experienced three SAEs, one of which was considered treatment related (herpes zoster infection). No thromboembolic events were reported. CPD7657 exposure increased in a dose-proportional manner. Low anti-CDP7657 antibody titres were detected in the majority of CDP7657-treated participants with no apparent impact on the PK of CDP7657. Conclusion Single doses of CDP7657 showed predictable PK in healthy individuals and patients with SLE and were well tolerated, with no safety signals of concern. These findings support further investigation of CDP7657 as a therapy for SLE.

Patients with acute heart failure who received ularitide had greater reductions in systolic blood pressure and in levels of N-terminal pro–brain natriuretic peptide than those receiving placebo but had no improvement in cardiovascular mortality. Acute presentation with new-onset heart failure and rapid worsening of preexisting heart failure are two of the most common causes of hospitalization worldwide. 1 The disorder in each case is characterized by intravascular volume expansion and ventricular distention, which may cause myocardial injury in the absence of coronary artery disease or occlusion. 2 – 4 Episodes are associated with an accelerated rate of disease progression; each hospitalization for heart failure increases the risk of subsequent admissions as well as the risk of death from cardiovascular causes. 5 The first few hours after the initial presentation with acute heart failure may represent a period of . . .

Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs. A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys. Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG, and no serious adverse events related to efgartigimod infusion were observed. Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases. Clinicaltrials.gov NCT03457649. argenx BVBA.

Luspatercept is a fusion protein aimed at binding TGF-β family members and reducing SMAD2 and SMAD3 signaling in patients with myelodysplasia with ring sideroblasts. In a randomized trial involving transfusion-dependent patients with lower-risk disease, transfusion independence for 8 weeks or longer occurred in 38% of patients in the luspatercept group and 13% of those in the placebo group.

The promise of bispecific antibodies (bsAbs) to yield more effective therapeutics is well recognized; however, the generation of bsAbs in a practical and cost-effective manner has been a formidable challenge. Here we present a technology for the efficient generation of bsAbs with normal IgG structures that is amenable to both antibody drug discovery and development. The process involves separate expression of two parental antibodies, each containing single matched point mutations in the CH3 domains. The parental antibodies are mixed and subjected to controlled reducing conditions in vitro that separate the antibodies into HL half-molecules and allow reassembly and reoxidation to form highly pure bsAbs. The technology is compatible with standard large-scale antibody manufacturing and ensures bsAbs with Fc-mediated effector functions and in vivo stability typical of IgG1 antibodies. Proof-of-concept studies with HER2×CD3 (T-cell recruitment) and HER2×HER2 (dual epitope targeting) bsAbs demonstrate superior in vivo activity compared with parental antibody pairs.

Patients with transfusion-dependent β-thalassemia were randomly assigned to receive luspatercept (a binder for TGF-β family member ligands) or placebo. During any 12-week period, a greater percentage of patients in the luspatercept group than in the placebo group had a reduction of at least 33% (70.5% vs. 29.5%) or at least 50% (40.2% vs. 6.3%) in the transfusion requirement.