Safety and activity of anti-CD14 antibody IC14 (atibuclimab) in ALS: Experience with expanded access protocol.

INTRODUCTION/AIMS: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 in an acute treatment setting. We provided long-term treatment with IC14 to individuals with ALS via an expanded access protocol (EAP) and documented target engagement, biomarker, safety, and disease endpoints. METHODS: Participants received intravenous IC14 every 2 weeks. Consistent with United States Food and Drug Administration guidelines, participants were not eligible for clinical trials and the EAP was inclusive of a broad population. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), IC14 levels, and antidrug antibodies. Ex vivo T-regulatory functional assays were performed in a subset of participants. RESULTS: Seventeen participants received IC14 for up to 103 weeks (average, 30.1 weeks; range, 1 to 103 weeks). Treatment-emergent adverse events (TEAEs) were uncommon, mild, and self-limiting. There were 18 serious adverse events (SAEs), which were related to disease progression and unrelated or likely unrelated to IC14. Three participants died due to disease progression. Monocyte CD14 RO increased for all participants after IC14 infusion. One individual required more frequent dosing (every 10 days) to achieve over 80% RO. Antidrug antibodies were detected in only one participant and were transient, low titer, and non-neutralizing. DISCUSSION: Administration of IC14 in ALS was safe and well-tolerated in this intermediate-size EAP. Measuring RO guided dosing frequency. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.

A Real-World Analysis of New-Onset Heart Failure After Anterior Wall ST-Elevation Acute Myocardial Infarction in the United States.

The 1-year incidence of heart failure (HF) after anterior wall ST-elevation acute myocardial infarction (STEMI) remains difficult to determine because of inconsistencies in reporting, definitions, and adjudication. The objective of this study was to evaluate the 1-year incidence of HF after anterior wall STEMI in a real-world data set using a variety of potential criteria and composite definitions. In a retrospective cohort study, anonymized patient data was accessed through a federated health research network (TriNetX Limited Liability Company (LLC)) of 56 US healthcare organizations (US Collaborative Network). Patients were identified based on the International Classification of Diseases, Tenth Revision criteria for anterior wall STEMI during the 10-year period from 2013 to 2022 and the absence of prespecified signs or symptoms of HF. Values for 1-year incidence were calculated as 1 minus Kaplan-Meier survival at 12 months after anterior wall STEMI. Univariate Cox proportional hazard ratio was calculated to compare risk associated with potential risk factors. The analysis utilized 5 different types of definition criteria for HF: Diagnosis codes, Signs and symptoms, Laboratory/imaging, Medications, and Composites. A total of 34,395 patients from the US Collaborative Network met eligibility criteria and were included in the analysis. The 1-year incidence of HF varied from 2% to 30% depending upon the definition criteria. Although no single criteria exceeded a 1-year incidence of 20%, a simple composite of HF diagnosis (International Classification of Diseases, Tenth Revision-I50) or use of loop diuretic produced a 1-year incidence 26.1% that was used as the benchmark outcome for evaluation of risk factors. Age ≥65 years, Black race, low-density lipoprotein ≥100 mg/100 ml, elevated hemoglobin A1c (7% to 9% and >9%), and body mass index≥35 kg/m2 were also associated with increased risk of HF. In conclusion, patients with anterior wall STEMI continue to be at high risk for new-onset HF. In the absence of structured, prospective, systematically adjudicated diagnostic criteria, composite definitions are more likely to yield accurate estimates of HF incidence.

Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis.

BACKGROUND: The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers. METHODS: In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor. RESULTS: IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33 days of follow up. CONCLUSION: IC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study. CLINICAL TRIAL REGISTRATION: NCT03487263.

The characterisation of human respiratory epithelial cells cultured on resorbable scaffolds: first steps towards a tissue engineered tracheal replacement.

In this study we have used lectin histochemistry and scanning electron microscopy (SEM) to assess the growth and characterise the differentiation of human respiratory epithelial cells (REC) cultured on two biomaterial scaffolds. The first scaffold, based on a hyaluronic acid derivative, was observed to be non-adhesive for REC. This lack of adhesion was found to be unrelated to the presence of the hyaluronic acid binding domain on the surface of isolated REC. The other scaffold, consisting of equine collagen. was observed to encourage REC spreading and adhesion. Positive Ulex Europaeus agglutinin (UEA) lectin staining of this preparation indicated the presence of ciliated REC on the scaffold surface. However, the marked decrease in peanut agglutinin (PNA) positive staining, relative to that of control cultures and native tissue, indicates a dedifferentiation of the secretory cells of the REC monolayer. SEM analysis of REC cultured on the collagen scaffold confirmed the presence of ciliated cells thereby validating the UEA positive staining. The presence of both established and developing cilia was also verified. This study indicates that collagen biomaterials are appropriate for the tissue engineering of REC. Furthermore, that UEA and PNA staining is a useful tool in the characterisation of cells cultured on biomaterials, therefore helpful in identifying biomaterials that are suitable for specific tissue engineering purposes.